How Valium works: in detail

This week, in Nature, the structure of a very important neurotransmitter receptor was revealed. The receptor, the GABA-A, allows the functioning nervous system to avoid the “brain super storms” that constitute epileptic seizures. When the neurotransmitter, GABA, binds to GABA-A, in synapses, in acts to inhibit neural activity. The inhibition of neural activity is critical to brain function because the brain can then compute in a very meta-stable state, quite like a marble on the edge of a saddle. That is one of the key design features of our brains that perhaps can be reverse-engineered someday for more power high performance computing a great energy efficiency.

It’s not surprising then, that the GABA-A receptor is also the target for some key drugs, like Valium and alcohol. Both of these drugs act to inhibit brain activity. When taken together with opioids, the effect is one of synergy and the effects can be deadly.

The paper by Zhu et al. used a technique called cryo-electron microscopy to reveal the detailed structure of GABA-A “frozen in the moment” of binding to a Valium analog. This is very important because it may reveal design hints at how to build a future Valium-like drug that relieves anxiety without sedation.

Counting action potentials

A very interesting (non-firewalled) paper by Chamberland et al in PNAS reveals a new kind of transfer logic for brain cells. The neural circuit is the first synapse in the so-called hippocampal tri-synaptic loop, an area of the brain that I’ve been very interested in from the standpoint of my own research. The usual suspects for informational transfer between neurons at the synapse are either frequency or timing encoding of action potentials. Here the author’s demonstrate a new type of encoding such that the post-synaptic neuron, a CA3 pyramidal cell actually counts the incoming number of action potentials to determine (decide) if it in turn, will fire an action potential.

Why is this important? How information is gated in brain circuits is crucial to how they compute on information (just as it is for non-biological digital computers). If we want to understand (from a reverse-engineering standpoint) how human brains do the cool things they do, then we have to be on the look out for phenomena like the one described here, because therein lies a clue to brain computation.

I’ll just add, that this neural circuit, the hippocampus, turns out to be crucial to learning and memory–particularly the kind called episodic, or what I describe to my students as “the movie of your life”.

AI and Video Gaming

Today’s FT has an interesting article(behind paywall) about AI being deployed into the video game space after its success at Chess and Go. What interests me here is that such video games are more open ended and ‘noisy’. They typically don’t have compact rule sets and strike me as capturing more of the flavor that smart machines are going to encounter in the real world (say when they are autonomously driving on the Washington DC beltway). Of course, the typical algorithm right now involves reinforcement learning and the AI plays against itself. That’s perfectly sensible in a gaming environment, but not really applicable to autonomous robot roaming out in the wild.

There’s a different approach out there and it’s based on reverse-engineering the brain processes that sub-serve hu man child language acquisition.  The key idea is that human children acquire language with great ease and not a lot of reinforcement. We know quite a bit about the neurobiology of mnemonic function, both at the molecular level and at the neuro-algorithmic level. That this existence proof manifests so saliently suggests to me that this is where the next paradigm is going to be revealed.

Adult neurogenesis? Not so much in humans

This is a huge result, making NPR and published in Nature, here. Since the discovery of adult neurogenesis in rodent models, it has been assumed by many (but not all) that we humans did the same thing. The assumption was that we grow new neurons every day throughout our lives.

Aside: actually that assumption was contrary to what many of us were taught. Before the discovery of rodent adult neurogenesis, it was thought humans stopped producing new nerve cells with the onset of adulthood.

The latest findings indicate that in humans, the production of new neurons slows down by age 7 and is gone by age 13. That’s shocking. What was the selection pressure for loosing such a phenotype from rats and mice?

The hazards of neuroX in k-12…

Popular neuroscience myths are now considered a risk to k-12 education in the UK, story here. Money quote:

“Teachers have a very enthusiastic attitude towards the brain, but there’s no neuroscience in teacher training at the moment and that makes teachers a little bit vulnerable to the very skilled approaches of entrepreneurs in selling products that are supposedly brain-based but actually are not very scientific in their basis and have not been properly evaluated in the classroom,” warned Dr Paul Howard-Jones, a leading expert on the role of neuroscience in educational practice and policy at the University of Bristol.

Applying to Doctoral Programs in Science II

The second piece of crucial advice for individuals considering applying for doctoral programs in the sciences here in the United States has to do with a separate letter from the formal application package. The addressee is a faculty member whose research interests align with your own. Or to put it more bluntly, a scientist for whom you can align your own ideas for a thesis with their established research program. The decision on who to select for this letter has been made infinitely easier by the Internet. But, nevertheless, the process takes some very hard work. Suffice it to say, the work is worth it. In my experience, if done well (and assuming you have decent grades and GRE scores) it will double your chances of admission with fellowship support.

So the first part of the research process involves going to the web site of the program (e.g. ours is here). Generally on the web site, you will find a listing of faculty members with a short precis of their research interests. This however is only the start of what you’re going to do in terms of producing a letter.

Look through the list. Besides looking for a match in terms of the science, you’ll also want to look for initial evidence of a successful lab. One very simple piece of evidence is tenure. In general all full professors have tenure. But a tenure-track faculty member (e.g. an assistant professor) can actually be running an even more productive and successful lab. To assess this, you’ll need to dive into Pub Med (web site is here). Search for you potential targeted faculty member (perhaps your future thesis advisor!) and look for the number and quality of publications. Quality is assessed by the impact factor of the journal (but a good sign are articles published in Science, Nature, the Proceedings of the National Academy of Science or one of the Cell Journals–such as Neuron). If your faculty member is more senior, then it’s a good sign that they are the last or senior author on the papers. If your target is junior, then they may either be first or last author, but in general, they shouldn’t be in the middle. Download some of the major articles for a serious read. We’ll get to that shortly.

Search the web now also for the lab’s home page. In most cases, you’ll get an idea of the make-up of the lab, a longer statement of the lab’s interests and crucially usually some photos of the lab members, either individually or as a group. Look carefully at the images–do the lab members look happy?

Now for the most difficult part: read the journal articles that you’ve picked very carefully. Note your questions in pencil along the side and assess the figures critically. Does the science still seem substantive to you? Do the methods seem interesting and doable in and of themselves?

Look at the references. Does the lab mostly cite it’s own work (not a good sign)? Note the major citations and download those papers also from Pub Med. Read them critically also.

Now produce your letter to the faculty member. Express your interest in joining the lab as a graduate student. Crucially, cross-reference, your application package to the program. The letter should address your own scientific interests within the context of the lab’s, it should demonstrate that you’ve read the relevant papers, and it should lay out your own ideas for next steps (potential thesis projects).

If you can, have a friend who is a scientist, read a draft of your letter. Incorporate any suggestions and email the letter directly to the faculty member. Don’t even think about using a mail merge program to send the same letter out to multiple faculty members.

You’ve just massively increased your chances of admission.

Applying to doctoral programs in science I

I keep giving advice over the years on how best to apply for doctoral programs. It’s time to put down at least the most central part of this advice as a service to loyal readers who, after careful consideration, have decided to go on to get their PhD in science. The advice here is somewhat localized (to use the computer software vocabulary): it applies best to my own field of neuroscience and the value of the advice probably tails off significantly as the discipline becomes further from my own. I’d also welcome comments on my advice (although, as always, I’ll moderate) because there may be valuable insights from other faculty members who are also readers of Advanced Studies.

So first piece of advice: understand that the costs of education at the doctoral level in neuroscience are counter-intuitive, especially to an undergraduate. The more established elite institutions (with the stellar undergraduate tuition costs) actually are the better economic deals for a doctoral student. That’s because they typically pay higher graduate student stipends and almost universally wave tuition. Sometimes they even subsidize housing (in expensive housing markets like Manhattan).

The result is that, in deciding where you want to apply for graduate school (in the hard sciences), don’t be scared off by what the undergraduate tuition costs may be. If admitted (with a fellowship and most folks are), you’ll be looking at probably full tuition remission and a substantial stipend. If you can get subsidized housing in addition, you’re earn your PhD with a small amount of savings and at least no debt.