Traditional neuroanatomy, in addition to filling the most demanding weeks of my education, has focused on area-to-area connectivity-the location and properties of gross anatomical areas and connections between them. The human brain, however, is composed of tens of billions of neurons each connecting to thousands of others. Traditional area-to-area connectivity is insufficient to capture the staggering complexity of the brain and its maladies.
Many of the most significant neurological disorders facing human society currently-Autism, epilepsy, depression and Schizophrenia-are not disorders where gross brain formation is compromised: they are disorders of information processing caused by the disruption of cell-to-cell connectivity.
Comparatively, one cannot understand a computer simply from an exhaustive description of its parts, be they large or small. Similarly, one cannot understand the brain simply by studying neurons in isolation or in large groups forming areas. In order to develop treatments for these disorders and better understand the healthy brain, a new generation of neurons in neuroanatomy is needed: a “wiring diagram” of neurons in the brain.
However, it is important to elaborate on what precisely is meant by a wiring diagram of the brain. The strictest interpretation calls for a matrix of connectivity between each cell in the brain. While this has been determined for the nematode Caenorhabditis elegans and its 302 neurons by Sydney Brenner and colleagues in the 1980s, the scale of the expansion to the human brain is mind blowing!
Additionally, this approach faces another substantial flaw best stated by Dr. Brenner himself. To paraphrase, simple organisms use the ‘European model’ of neural development with a neuron’s genetic lineage determining its function in the brain. More complex organisms, including mammals and humans, use the ‘American model’ of neural development where a neuron’s function is determined by neighboring neurons and exposure to protein growth and survival factors. These random factors influencing the fine detail of brain development prevent the comparison of strict wiring diagrams across subjects, greatly limiting their usefulness.
Recent research into wiring diagrams has focused on the probability of connectivity between different classes of neurons. Due to limitations of the technique used to evaluate connections, only up to a few cells within a small area are tested at any one time. This misses the many important inputs to a neuron which are far away. Furthermore, gathering these experiments into a larger wiring diagram depends strongly on the difficult task of assigning each neuron to the most relevant class.
Fortunately, with a computer we know that it is composed of transistors, capacitors and resistors assembled into microchips and eventually into components such as a graphics card and central processing unit (CPU). There are many, many ways in which one could differentiate different types of neurons. One might draw the lines along the dimension of what neurotransmitter a neuron uses to communicate, genetic markers expressed, physiological responses to sensory stimuli or the shape of the neuron, to name a few. If one wanted to assemble an anatomical wiring diagram of the brain, as many neuroscientists do, one of the most effective paths might be to assemble these cell classes into small modules which could then make up the circuitry of larger areas.
To illustrate this type of assembly, let us consider the neural cells in the retina. The flow of information through the circuit is very simple: photoreceptors pick up light from a single point in space then transfer this information to the bipolar cells which combine information with neighboring bipolar cells through the horizontal cells. This spreading of information laterally occurs again through amacrine cells when the bipolar cells pass information to the retinal ganglion cells.
We can see a very simple module composed of a single bipolar and retinal ganglion cell surrounded by horizontal and amacrine cells is tiled redundantly throughout the retina. However, if we examine the cells more finely we can see that there are many different flavors of this module due to many shapes and genetic fingerprints of the cells which make up the module. However, we find that each of these flavors of module forms a mosaic which covers the visual field just once! The retina is very similar to many cameras taking a picture with different filters: light edges, dark edges, color, and movement to name a few.
This mosaic of modules pops out beautifully in the retina, but the neatly organized circuit decays into a tangle of wires when we look into areas higher in the brain. Neuroscientists are hard at work teasing more modules of neurons out of the complexity of the brain to tell us more about what we are as humans and how we can treat neurological disorders that are currently black boxes to the medical field. Although computers and the human brain accomplish starkly different tasks, but we need wiring diagrams to understand each of them!
