Thursday, 13 March 2014

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...

Thursday, 2 January 2014

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...

Sunday, 9 June 2013

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.

Wednesday, 8 August 2012

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.

Wednesday, 9 May 2012

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.

Thursday, 26 April 2012

Towards an artificial engram

Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K, Tonegawa S (2012) Optogenetic stimulation of a hippocampal engram activates fear memory recall. Nature.

Tim Bliss and friends recently wrote about the possibilities of using fancy genetic tools to test the hypothesis (quite an old hypothesis too) that memories are encoded in networks of neurons whose synapses have been modified by LTP-like plasticity (Neves, Cooke & Bliss, Nat. Rev. Neurosci. 2008). This week's Nature has a remarkable paper from the Tonegawa group, where they have made a big step forward along this path. They used a clever combination of transgenic mice and virus transfection techniques to produce a mouse where activated neurons in the dentate gyrus (DG) of the hippocampus are not only labelled with YFP but also (and here's the powerful bit) express light activated sodium channels (ChR2). They found that fear conditioning labelled a subset of neurons in the DG, and what's more, that activating this set of neurons a few days later (by shining blue light into the hippocampus), even in a different context to the original conditioning, produced the freezing reaction that you see in fear conditioning.

So, a significant step forward in the quest for the engram. It's interesting to ponder how accurately this result reflects how memory operates in the intact animal. You might expect that more than the DG is involved, for example. Would it be possible to do similar experiments with similar results in CA1 or CA3? And what about other forms of memory, such as episodic memory, would they work in a similar way?

Friday, 13 January 2012

Presynaptic NMDA receptors

Presynaptic NMDARs in the Hippocampus Facilitate Transmitter Release at Theta Frequency
McGuinness et al 2010 (Neuron)

This paper comes from the group of Nigel Emptage in Oxford, who has agreed to take me on for a short placement this summer. So I should probably be careful what I say! However, this does really strike me as a well presented paper with a strong story about the presynaptic role of NMDA receptors.

In rat hippocampus organotypic slices, they patched a CA3 pyramidal neuron and filled it with a calcium-sensitive dye, which enabled them to stimulate action potentials in the cell and observe calcium transients in boutons synapsing onto neurons in CA1. Using fancy stats, they identified less frequent large-amplitude transients which were abolished by the NMDAR-blocker AP5. Perfusing the cell with norketamine, an internal NMDAR blocker also abolished the large transients, confirming that this is definitely a presynaptic phenomenon. Some EM pictures confirm that NMDARs are present at both sides of these CA3-CA1 synapses. They also used glutamate uncaging (my pet technique!) to show that presynaptic NMDARs can produce inward currents visible back at the soma. And in a nice coda, they started to explore the physiological relevance by showing that these large calcium transients are more frequent after induction of LTP by theta-burst stimulation.

So the idea is that a large calcium transient corresponds to the release of a glutamate vesicle at the bouton. This is stochastic - it doesn't happen every time. The kinetics seem to be fast enough to allow for the displacement of magnesium to open up the NMDAR channels within the duration of a single action potential.

Caveat: this work was done in organotypic slices after 7 to 14 days in vitro, so may be more relevant to the physiology of the developing than the adult brain.