The Brain Wave: Scientists unravel the brain’s synaptic anatomy

Communication between different neurons provides the functional basis for how the nervous system works. For example, neurons in the retina relay visual information to higher-order neurons in the cortex to derive our conscious perception of the external world. As a result, understanding which neurons talk to each other is fundamentally necessary for gaining insight into the biological basis of brain function. One way to understand how neurons connect with each other is through tracing their connectivity patterns. Each neuron sends its axon, a wire-like protrusion, to a nearby or far-away neuron. Electrical ripples known as action potentials travel through the axon to reach the axon terminal, triggering release of chemicals called neurotransmitters. These neurotransmitters will bind to receptors on the adjacent neuron’s dendrites. The functional contact between each neuron is a synapse. As a result, tracing where these axons go can provide a clue to which populations of neurons communicate with each other, and ultimately, a better understanding of the brain’s anatomical wiring diagram. For a long time, tracing was done via injecting a dye that moves throughout neuronal processes. These reagents could either travel backward (retrograde) or forward (anterograde). By following where the dye ends up, it is possible to figure out which region the injected neuron is projecting to, or which neuronal population is sending information to the injected neuron. However, these classical dye tracers suffer from a major drawback. They do not prove the existence of synapses, since localization of the dye at an area does not necessarily imply the presence of synaptic connections. As a result, scientists needed a type of tracer that could not only traverse through axons but also jump across synapses. To that end, rabies viruses have been utilized as tracers due to their ability to infect a large number of neurons via synapse jumping. In addition to providing proof that synapses exist between neurons of interest, another benefit to the rabies virus is that it can be used to map longer pathways that involve more than two distinct populations of neurons. However, the results can be extremely difficult to interpret, since it is difficult to control the number of synapses that the virus crosses. As a result, tracing experiments that utilize rabies viruses must have clearly delineated timelines so that the chronological order by which synapses were crossed can be determined. Recent developments in genetics combined with viral technologies have made vast improvements to rabies virus tracing. By swapping out the comments necessary for infection and transsynaptic spread, the modified version of rabies virus can now only jump one synapse. The new technique is also much more precise because the virus can now infect only neurons that express the necessary molecular components, whereas before, the virus could infect any cell in its vicinity. Termed transsynaptic viral tracing, this technology was first used to trace the brain’s olfactory pathways. The importance of tracing methodologies cannot be overemphasized. The brain is a biological entity composed of interconnected neuronal populations. As a result, the first step toward understanding the circuit mechanism of brain function is to obtain a map of the wiring diagram. This could later lead to developments of brain diseases in which neuronal circuits are perturbed.