Transneuronal tracing – rabies virus excels!

Transneuronal tracing – rabies virus excels!

The National Institutes of Health has made it a major goal to define the connectome, that is, how all the parts of the central nervous system (CNS) are connected to, communicate with, each other.  This is critical information if we are to understand ourselves, our mental processes and how the CNS mediates the expression of those processes.  And, it is critical if we are to understand how those processes can go awry or, like rage, perilously surprise us.  The rabies virus can be a very important tool in defining the circuitry of the CNS because of its unique ability to infect, without damaging, almost all the regions.

A number of neuroanatomists, scientists working to understand how the parts of the CNS communicate with each other, have found the rabies virus to be a nearly perfect tool for identifying connections.  They have taken on the risks of working with the deadly virus because it is such a unique and powerful tool.  People working in these labs must be vaccinated against rabies, and the strength of their immunity against the virus rechecked frequently.  It is an enormous commitment to better our understanding of ourselves.  Below is an excerpt from a review by just one of these intrepid investigators.

“Powerful transneuronal tracing technologies exploit the ability of some neurotropic viruses to travel across neuronal pathways and to function as self-amplifying markers. …rabies virus is the ideal tool for studying motor innervation, since its peripheral uptake occurs exclusively at motor endplates. Rabies virus is the only viral tracer that is entirely specific, as it moves exclusively across chemical synapses by strictly unidirectional (retrograde) transneuronal transfer without altering neuronal metabolism, allowing for the stepwise, time-dependent, identification of neuronal networks across an unlimited number of synapses.” [Advances in viral transneuronal tracing. Ugolini G., J Neurosci Methods. 2010;194:2-20. PMID:20004688]

As I’ve written before, rabies is very unique in that it specifically infects neurons (nerve cells) of the CNS.  It does not infect sensory neurons or neurons of the peripheral autonomic nervous system, and, it does not infect any other cell that we know of.  It is, in a way, a perfect storm.  Moreover, infection of neurons by rabies does not lead to damage of those neurons.  It uses the neurons to replicate/to multiply and to move along, but without evidence of damage to them.  To do its job, to turn new victims, it must maintain the basic operation of the CNS, only redirecting it to become a lyssant, a rage machine.  The rabies virus does not burst out of the neurons as many viruses do from the cells they infect.  Amazingly, when newly synthesized viral particles do leave a neuron they have infected, they do so only at the neuron’s normal communication sites, called synapses. 

At these synapses, specifically chemical synapses, two neurons come very, very close to one another.  The two communicating neurons create specializations that allow the ‘first’ neuron to release chemicals, neurotransmitters, which will attach to receptor molecules on the ‘second’ neuron.  The second neuron will use the attachment/binding of those chemicals as a means to detect and transmit the signal on to additional neurons.  The synapses also use various means, such as trophic factors and adhesion molecules, to maintain the specializations and to keep them located directly across from one another so that communication is optimal.  Rabies uses these communication ports to move from neuron to neuron, disrupting the normal flow of information to direct its host to go out and turn additional victims – all so that the virus can survive. 

I believe, but am speculating, that the receptor that the rabies virus uses to initially infect skeletal motor neurons is exactly the same as the one that it will use to be taken up into, infect, each new neuron.  I can’t imagine that the extreme selectivity that limits the virus to only infecting the presynaptic endings of skeletal motor neurons will not be maintained at each synapse that the virus crosses.  Therefore, it is this receptor and the brain circuits it controls that are the key to us understanding lyssantic behavior, be it intermittent explosive behavior or a human werewolf.  And, once again we come back to wonder why this receptor has not been discovered.