Engineering a memory?

A recent Nature paper from the Malinow lab in San Diego has attracted a lot of attention. Entitled "Engineering a memory with LTD and LTP", it describes how optogenetic stimulation of auditory inputs to the rat's amygdala were paired with mild foot shocks to produce a conditioned fear response.

Optogenetics is a genetic trick which allows the neuroscientist to activate a neuron with a flash of blue laser light. It's very trendy right now. The amygdala is a brain centre concerned with emotion, and particularly fear. You may have heard it mentioned a few times on "Firefly".

The clever thing is that the investigators were able to break this conditioned link between the blue flash and the fear response by applying a protocol called LTD to the auditory inputs, using the same optogenetic flashes but arranged in a very specific time sequence that has been known for many years to produce long term depression (LTD) at an individual synapse. Moreover, another protocol called long-term potentiation (LTP) could restore the erased fear conditioning. So it seems as though an acquired memory (in this case an association between a particular auditory input and fear) can be turned off and on at will by a bit of clever manipulation of synaptic strengths. This seems very close (at first sight) to claiming that we have discovered how to create or erase memories at will by strengthening or weakening individual synapses.

I have a couple of questions about this paper. First, why is fear conditioning so popular as an experimental model of memory? Surely there must be less unpleasant (for the rat) and just as robust protocols for producing associative memory. My friend Z tells me that fear conditioning is popular because the relevant circuitry is well understood, and the association can be produced with a single trial, so maybe not.

Second: does this experiment tell us much about how or even where this associative memory is encoded? After all, we can manipulate the strength of the synapse between an incoming auditory fibre and  its postsynaptic target in the amygdala, but the actual site of the associative memory is not necessarily that synapse, it could be much deeper in the network, perhaps several synapses further along the chain, maybe not even in the amygdala at all.  All that the LTP and LTD protocols are doing is "gating" the first synapse in the chain, allowing or preventing the incoming auditory signal to proceed further into the network. But the actual locus of memory formation is most likely elsewhere in the network, further down the chain of synaptic connections.



Nabavi S, Fox R, Proulx CD, Lin JY, Tsien RY, Malinow R (2014) Engineering a memory with LTD and LTP. Nature 511:348–352.

Finally

I feel I can finally write about this. After all, I got the certificate in the post the other day. I think that means they're not going to take it away from me.

The other day I was walking to the station with Sue, a pleasant walk along the riverbank. I remarked that this might be a nice way to start the journey to London on my viva day.  Sue had to point out that I had already done my viva a few weeks before, it was in the past, no longer in the future.

It's been like that, especially for the first few weeks after.

This thing has been on my horizon for so long, a fearful ordeal to be faced in the future, a background anxiety every day of the months I spent writing my thesis. It seemed like a permanent feature of my mental landscape. When it was finally over and done, it was unexpectedly difficulty to remove it from my future and place it where it belongs, in the past. As far as my brainstem and limbic system were concerned, it was all still to be done.

Still, I think I'm finally getting over it now. Even my reptile brain is feeling more relaxed.

The viva itself was tough. A Tuesday in early April, I was in that windowless little meeting room for 5 hours. The questioning was friendly but thorough. Every little discrepancy I had hoped might go unnoticed was ruthlessly dug out and exposed, shrinking, to the light. The folks outside, waiting with the champagne flutes and snacks, were a little restless by 6pm when I finally stumbled out, ashen-faced and mute.

Looking back, I think I pretty much lost hope halfway through. With the front of my mind I was still fielding the questions, but the back of my mind was already busy assessing options for alternative employment. I wonder if the Thirsty Meeples cafe needs another rules explainer? I was a bit gobsmacked when at the end my inquisitors exchanged a glance, then turned to me and held out their right hands. "Congratulations Dr Haslehurst!"

Limbo

I've come to a strange hinterland between two modes of existence. I finally handed my thesis in at the UCL student admin centre a couple of weeks ago, and I'm nervously awaiting my viva in 11 days time.  I've also started my postdoctoral job, but until I have passed through the dark valley of the viva I can't actually call myself a doctor. So it's an odd in-between place, neither one thing nor the other. No longer a student, but still not finished with the PhD process.

I'm hoping that the viva might actually be fun, once I get past the initial nerves. I have two excellent examiners – Prof Juan Burrone of KCL who is well known for being a genial chap and has done some milestone work on homeostasis, and Prof Tim Bliss, whom I once named the Bob Dylan of synaptic plasticity, Fellow of the Royal Society, inventor of LTP, and an extremely nice man. Of course they are both scientists, so if there are gaping holes in my work it will still be their duty to point them out, no matter how nice they are, but I'm hoping at least they won't kill me for sport...

Another year, and still not quite done!

I began writing my thesis in August last year, planning to take 4 months over it and submit at the end of October, just as my funding ran out. I felt pretty confident at that point, having produced more data in the previous 12 months than I had in the whole of the rest of my PhD put together (a common experience at the end of a PhD I gather). Not only had I repeated my UCL experiments with better resolution and positive results, I had also done some followup experiments including a pretty cool attempt to trace the flow of calcium signalling along the dendrite. However, half way through the writing process N (my Oxford supervisor) sent me back to the lab to collect some more data. Not enough weight to my thesis. So that set me back a couple of months. Humph. Probably a good call though, I'm a lot happier with my new, weightier thesis.

Anyway, I finally got it all written a week before Christmas, and there's just another round (or two? please God not three?) of supervisor feedback to get through. Submission in January is what I'm aiming for, then on to the world of post-docking. Still pinching myself sometimes – taking a year out to do a neuroscience Masters for fun has certainly taken me to unexpected places...

Walking to Oxford

Last week I walked from London to Oxford. Sue and I started at our old front door in Tottenham, had breakfast and a cup of tea with our old tenants, then walked west and south through various London parks (Alexandra, Highgate, Hampstead, Primrose Hill, Regents, Hyde), joining the Thames Path at Battersea and following it until we reached our new front door in Oxford. It's a journey that takes an hour on the train – it took us 9 days on foot. This journey was a way of marking our transition from our life in London to our new life in Oxford, a transition that began with a 10 week placement in a fantastic neuroscience lab in the Dept of Pharmacology at Oxford. This temporary stay here has morphed, quite unexpectedly, into a 2-year postdoc position in the same lab, preceded by me (hopefully) finishing my PhD here instead of at UCL (although I am still officially a UCL student). Very exciting for me – I love the city, I love the lab, and I love the work this lab does – but a big step for Sue, poor thing, who has had to give up her job as a church leader and move with me to Oxford where she must start again with house, work, church, and networks of friends. She's been courageous and cheerful through the whole process so far – her supportive attitude has made my whole neuroscience adventure possible, from the tentative beginning to where I am now.

Privilege

Here I am in Oxford, working for 10 weeks in the lab of a very distinguished neuroscientist. So I get the opportunity not only to learn sharp electrodes, do uncaging experiments with the latest equipment, and get to know some very clever people, but also to go punting on the Cherwell, browse in Oxford's extensive bookshops, and investigate the local ale houses. I feel very privileged.

In fact my whole neuroscience career to date feels like an enormous privilege. Doing a full-time Neuroscience Masters at KCL was a wonderful escape from a career that was slowly choking the life out of me. While I was there I was lucky enough to get a lab project  where I got some great mentoring in patch-clamp electrophysiology. Next came a frustrating period of knocking on closed doors, but eventually I was offered an RA job at UCL which swiftly metamorphosed into a 4-year PhD studentship, in a friendly lab doing a project I'm really excited about. And all the nice things that came along with that! – the SfN meeting in San Diego, the microelectrodes course in Plymouth, the imaging conference in Roscoff, and now Oxford. And all this funding! – my BBSRC studentship, a topup from GSK, travel grants, funded places.

Which brings me to the question that sometimes troubles me: is all this wasted on me? After all, I'm 53. I'd like to work until I'm 70, but even so, that only leaves me 15 years or so into which to cram a neuroscience career. Even if things go very well, that's hardly enough time to get my own lab. Not that I'm too worried about the own lab thing – I'd be very happy indeed with a few post-doc positions doing some cool work on synaptic plasticity. But still, the people who provided all this funding probably had 20-somethings not 50-somethings in mind – bright young people who could be trained up to provide a full working lifetime's contribution to the scientific life of the country. So what the hell do I think I'm doing here?

Well, I could wave my hands and talk about life, work and business experience, maturity and ability to get along with people,  habits of organisation and self-management. And you might respond with the distractions of family and property that accumulate with age, the increased risk of health problems, the tiredness and cynicism that sometimes cling to the middle-aged. Then I would talk about the huge proportion of science PhD graduates who do not go on to a career in science – it must be at least 50% I would guess – and that I have shown my commitment to this path by giving up a well-paid career in IT to follow it. So the return on my funders' investment might be smaller but it's also a lot more safe.

That's how I justify myself to myself. So, I'd better knuckle down and make this project count for something.

The four-minute neuroscientist

My friend Tim Allsop is currently playing Roger Bannister in an outdoor play which recreates his record-breaking run on the Iffley Road athletics track in 1954. As part of his preparation for the role, Tim met the great man, and found that he was rather bemused by his status as a sporting icon. He would much rather be remembered, apparently, for his research in neurology. His Wikipedia entry contains barely a hint of Dr Bannister's research career - it's all about that glorious 4-minute mile. A quick search on Google scholar reveals that his scientific interest was focussed on diseases of the autonomic nervous system, on which he published widely. From my perspective as a humble PhD student (who is currently training for the Hornsey 10K run!) I can understand his feelings. It seems to me that the commitment and hard work required to get a productive scientific career going probably makes training for an athletics record attempt pale into insignificance by comparison.