Thursday, February 21, 2013

Mind-blower: epigenetics makes memories

Do you remember your five-year-old birthday party? How about your wedding? Emerging science argues that you can do so because those experiences turned off genes at the time in a certain set of nerve cells in your brain. Stranger still, nerve cells may have this capability because they have re-purposed epigenetic mechanisms that other human cells use to "remember who they are."

To back up for a moment, epigenetic mechanisms are chemical changes that turn genes on and off without changing the genes encoded in DNA that we inherit from our parents. Research in recent years has established that they lend an extra layer of regulatory finesse to human genetics and make our complexity possible.

Epigenetics first made a splash in developmental biology. Researchers realized that while we have the same set of genes in every one of our cells, we develop 250 different cell types by the time we are born. Epigenetic mechanisms switch off a different set of genes (and leave a certain set on) in each cell type to result in the 250 types.

Stem cells that become bone or blood or liver cells as we develop "remember" their specialized nature, and they pass that memory on to their descendants as they divide and multiply in the constant turnover under way in most human organs.

This genetic memory is known to be accomplished by epigenetic mechanisms like methylation, the chemical attachment of a methyl group (one carbon and three hydrogens) to certain spots on the DNA chain. The process can turn surrounding genes off (prevent gene expression), while demethylation can turn them back on in an ongoing back and forth.

It really gets fascinating when you consider that the nerve cells making up the brain, unlike nearly every other human cell type, never divide and multiply, and so they never pass on genetic memory. One theory on this is that nerve cells have put their genetic memory mechanisms to another purpose: remembering.

Most of this is theoretical of course, and it is the subject of intense study in the lab of David Sweatt, Ph.D., chair of the UAB Department of Neurobiology and director of the Evelyn F. McKnight Brain Institute here. He sat down with The Mix to discuss his presentation at a recent UAB Epigenetics Symposium about how nerve cells may have evolved to store memories.

Show notes for the podcast:

1:47 Sweatt's lab explores the role of epigenetics in the adult human brain. That has required a re-definition of epigenetics, a science once thought pertinent only to cells that divide and multiply, and that pass on epigenetic marks to their descendants. Nerve cells in the brain do not divide, multiply or turn over as a population, and yet, epigenetics mechanisms are at work. The field now recognizes that such mechanisms contribute to learning and memory.

4:14 The genetics and epigenetics of inheritance has finally answered one of the most long-standing questions in human history: how are traits passed down from parents to children? Epigenetics in neurobiology is also answering another longstanding, philosophical question: What makes us who we are? It turns out that epigenetic mechanisms "sit at the interface" of nature (genes) and nurture (environmental factors make epigenetic mechanisms that turn genes on and off).

5:58 Epigenetics have provided for scientists a fundamental answer for how a single transient experience can make a permanent change in the biochemistry of the brain. It is no small thing that we are now beginning to understand this once-mysterious process.

8:10 Methylation is the mechanism that silences perhaps half or three-quarters of the genes in the human genome to make a nerve cell a nerve cell. Those changes are life-long, and so that set of silenced genes is the same in that family of cells for a lifetime.

12:02 A foundational discovery made in other labs in recent years is that epigenetic changes to nerve cells are necessary for humans to remember things for the long term. Once the field knew that, they could begin to try to understand the mechanisms.

12:35 If anyone who is listening to this podcast today remembers it tomorrow,  it will be because of changes in the genes being expressed in the nerve cells of their brains as they listen. There is a continuous, dynamic interplay between our experiences and the parts of our genes recording memories. Epigenetic mechanisms are powerful regulators of gene transcription and translation, and appear to have been applied by evolution to the problem of storing memories.

13:22 If evolving nerve cells could talk, they might have said, "OK, I have to control which genes are turned on and off in certain nerve cells to store memories, what is the toolbox I have at hand to accomplish this?" It's the same toolbox of epigenetic mechanisms it uses to control gene expression in general.

13:35 Methylation has been been mentioned as part of the toolbox. Then there is histone acetylation. DNA does not just float around in the nuclei of human cells, but is instead wrapped around protein "spools" called histones that help to organize, protect and regulate them as part of a larger package called chromatin. Part of DNA regulation is spatial, and works by controlling when certain parts of DNA chains are able to unravel from their spools. The unraveling makes a stretch of code accessible to the protein-making machinery. Attachment of an acetyl group (a methyl group plus an oxygen) to a histone tends to make genes on that spool more accessible. In addition, there is phosphorylation and ubiquitination, processes that now appear to regulate both chromatin in general and behavioral memory formation.

14:51 With environmental factors (sunlight, smoking and pollution) known to make epigenetic changes, many labs are trying to determine whether such changes have roles in many diseases. Humans have a protective compartment surrounding their brains that screens out many toxins called the blood-brain barrier.

16:23 Sweatt's presentation at the UAB epigenetics symposium discussed how he is working to determine the exact biochemical mechanisms by which methylation is changing the firing patterns of nerve cells to endow networks of nerves with the ability to store memories. What are the exact and ongoing patterns of active methylation and demethylation as the brain reacts to sensory experiences?

18:00 To study the process of memory formation, Sweatt's lab examines certain classes of basic memories that we share, presumably, with study animals like mice. For instance, to survive, our animal ancestors would have had to be able to remember which places were dangerous and which offered food or security (spatial recognition of surroundings).

19:02 Humans appear to have "place cells" in our hippocampus, the part of the brain that tells you where you are and where you have been. When you walk into a new room, or even a new place in a room, a particular set of hippocampal neurons fires in certain patterns in such a way that allows the brain to record a 3D map of that place. Different cells fire when you are in different places. One experiment under way in Sweatt's lab is seeking to test whether certain DNA methylation patterns enable those cells to record that sense of place.

21:27 All this research is ultimately aimed at understanding the normal brain so as to come up with new treatments for those with disorders that affect memory (dementia, Alzheimer's, etc.) and learning. Sweatt's lab and many others are seek to build the framework for the development of new molecular targets for new kinds of drugs.

The previous three podcasts in this epigenetic series were Epigenetics has impact on health beyond DNA, Epigenetics, aging and cancer and Obesity, exercise and epigenetics: no excuses.

Dr. Sweatt’s research is largely funded by the McKnight Brain Research Foundation.

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