Sunday, June 11, 2017

On Learning and the Epigenome aka. Some Cool New Work Out of My Workplace

The question of how memories are made, stored and retrieved is something that has fascinated me since my undergraduate days.
Our genetic 'recipe' is far more complex than I think any one back when the first draft human genome was finished could have predicted. There's a four letter code, followed by a layer of modifications that in themselves are numerous, and the whole thing can interact with proteins and itself in time and space. It's code + 3D structure that also responds to real time environmental changes. Yes, the genome is amazing. And now, thanks to great techniques and some scientists who think big, the dynamic thing that is our genome is being shown to be linked to memory formation and maintenance.
Many of you will have heard of the term 'epigenetics'. Epigenetics is the term for the chemical modifications that are made to DNA bases that change how the bases of DNA are used. It's an additional layer to A,C,Ts and Gs of the code. And just like the code, it can differ between people, but it's not just what you inherit, it can change depending on what a person is exposed to - it also can change in 'real time'.
Neurons in the brain with visible dendrites.
Credit: Yinghua Ma, Timothy Vartanian (The Cell Image Library)
Epigenetics is quite the buzzword, and there's been some big work around it - things like cigarette smoking being linked to changes in the epigenome - so if you smoke the way your DNA is regulated is altered. And now, well, this is where it gets really, really cool - awesome colleagues of mine have just shown that learning changes a certain type of epigenetic mark in neurons.
It gets even more interesting - this particular epigenomic mark (m6dA, a modification of the adenosine, or the A base) is associated with something called fear extinction. Fear conditioning is a learned behaviour, and works just like the famous Pavlov's dog experiment, where a stimulus is associated with an outcome - except in this case it's negative, and an individual (usually a mouse) learns to associate the stimulus with something terrible and ends up showing fear when presented only with the stimulus (it can be light, noise, something they see). The mouse is then exposed to the stimulus, but nothing happens - eventually the mouse learns that the stimulus will result in nothing negative, and doesn't get scared - their fear of the stimulus is effectively extinct.
Why is this important? Because it's good to understand memory. And what makes the brain work. And we know very little about our minds! But it may also have applications when things go wrong. A leading theory of PTSD is that the mechanisms of fear extinction are faulty, and that instead of re-conditioning to no longer have a primal fear response to a stimulus, a person with PTSD goes into the fear response with no control. If we understand how fear extinction works, it gives scientists a starting point in designing ways to treat and fix this faulty mechanism. Linking epigenetic changes to learned response and fear extinction therefore, could be a key piece in treating a terrible mental disease.
So overall - this paper is awesome - not only for the fact that Li and co. have shown that this epigenetic mark exists in neurons, not only for the cool techniques used, not because it's epigenetics but also because it's one more piece in the complex puzzle of memory and adds to our understanding of what memory is and just how we could start to think about treating conditions around memory and learned behaviour. Really neat stuff and it's awesome to see them doing this cutting-edge work every day at QBI.
And for those out there wanting to read the full paper, it's up on bioarxiv!

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