Despite our best efforts, we still have no idea how the brain works. It must have something to do with the circuitry – the connections – and the tiny electrical impulses, but how that combo results in experience, perception, cognition is a mystery. Not only do we have no idea how it works, we don’t really know what the brain looks like. To the naked eye, the organ itself is a convoluted mess, and once you throw it under a microscope and zoom onto the cellular level things only get worse – to the point where we can’t really figure it out. Some groups are starting to assemble comprehensive pictures of the cellular architecture and connectivity in very small brain areas, but the resulting picture is still a mess – mind you a powerful mess that seems to actually be able to do brainy things when modeled with a supercomputer, but a mess nonetheless.
So to simplify things maybe we should try starting with single cells and their connections?
Thankfully, a new technique that will allow us to do this is currently in the pipe, with only a few kinks left to be worked out. The technique employs a modified version of the rabies virus that forces neurons it infects to produce a red fluorescent protein called mCherry. MCherry makes the infected cells glow red so they are visible under a microscope. The key though, is the rabies virus itself. Although this bug is renowned for turning otherwise friendly animals into froth-mouthed killers, in the neuroscience world it’s famous for its ability to infect neurons and then jump to others through synapses. This means that rabies will only infect neurons that are attached to one another, so if you can somehow trace where the rabies virus goes – ie with something like mCherry – you can trace a neural circuit on the cellular level. Unfortunately, since neurons are so massively interconnected, left unchecked, an mCherry-rabies infection will result in a tangled red mess that is impossible to make any sense out of. (Recall the X-hundred trillion synapses in your brain.)
By putting a new spin on this approach Ian Wickersham, Aldis Weible and respective colleagues do away with the problem of the tangled red mess. Through a series of studies employing some complex genetic manipulations (in mice), these guys have made 2 major changes to their rabies virus:
1. They engineered rabies so that it only infects specific types of neurons – and using special mutant mice they can direct the infection to different types of neurons.
2. The modified rabies can only cross from the initially infected – or first order neuron into the neurons directly connected to it – the secondary neurons.
The result is a modified rabies virus that exposes the connectivity of specific types of neurons, and given the right circumstances it may actually allow us to fully investigate things like which and how many neurons synapse onto a single cell. At the moment though, we can’t put our irrevocable trust in this virus.
The main problem is that it is currently impossible to be sure whether the initial infection is in many neurons or a single neuron, potentially making it difficult to interpret the resulting pictures.
Never fear though – this virus is definitely a step in the right direction. Another iteration and this modified rabies should be ready to shake things up as far as single cell connectomes go.
For more, including refs, see In Depth.