Each new generation of astronomers discovers that the universe is much bigger than their predecessors imagined. The same is also true of brain complexity. Every era’s most advanced technologies, when applied to the study of the brain, keep uncovering more layers of nested complexity, like a set of never ending Russian dolls. We now know that there are up to 1,000 different subtypes of nerve cells and supporting actors—the glia and astrocytes—within the nervous system. Each cell type is defined by its chemical constituents, neuronal morphology, synaptic architecture and input-output processing.
Different cell types are wired up in specific ways. For example, a deep layer 5 pyramidal neuron might snake its gossamer-thin output wire, the axon, to a subcortical target area while also extending a connection to an inhibitory local neuron. Understanding how the brain’s corticothalamic complex creates any one conscious sensation necessitates delineating these underlying circuits for the 100 billion cells in the brain.
Bulk tissue technologies such as functional brain imaging or electroencephalography identify specific brain regions related to vision, pain or memory. Yet they are unable to resolve details at the all-important circuit level. Brain imaging tracks the power consumption of a million neurons, irrespective of whether they are excitatory or inhibitory, project locally or globally, and so on. For progress on consciousness, something drastically more refined is needed.
Furthermore, as our understanding of the brain grows, our desire to intervene, to help ameliorate the many pathologies to which the mind is prey, grows commensurately. Yet today’s tools (drugs and deep-brain stimulations) are comparatively crude, with undesirable side effects.
To the rescue rides an amazing technology, a fusion of molecular biology with optical stimulation, dubbed optogenetics. It is based on some fundamental discoveries made by three German biophysicists—Peter Hegemann, Ernst Bamberg and Georg Nagel working on photoreceptors in ancient bacteria. These photoreceptors directly (rather than indirectly, like the ones in your eyes) convert incoming light in the blue part of the spectrum into an excitatory, positive electrical signal. The trio also isolated the gene for this protein, called channelrhodopsin-2 (ChR2). Bamberg and Nagel subsequently engaged in a fruitful collaboration with Karl Deisseroth, a professor of psychiatry and bioengineering at Stanford University, and Edward S. Boyden, now at the Massachusetts Institute of Technology.
The group took the ChR2 gene, inserted it into a small virus, and infected neurons with this virus. Many of the neurons took up the foreign instructions, synthesized ChR2 protein and inserted the photoreceptors in their membrane. In the dark, the receptors quietly sit there, with no discernible effect on their host cells. But illumination of the network with a brief flash (10 milliseconds) of blue light causes each of these bacterial photoreceptors to jolt their host cell a bit. Collectively, they reliably and repeatedly produce a spike in the membrane voltage. Spikes are the universal all-or-none pulses used by all but the tiniest nervous systems to communicate information among neurons. Each time the light is turned on, the cells spike reliably, exactly once. Thus, an entire population of neurons can be manipulated by precisely timed stabs of light.
The biophysicists added another photoreceptor to their tool kit. It derives from a different type of bacterium, one living in dry salt lakes in the Sahara Desert. Shining yellow light on it yields an inhibitory, negative signal. Through the same viral strategy, both photoreceptor types were then introduced into neurons. Once the neuron stably incorporates both types into its membrane, it can be excited by blue light and subdued by yellow. Each blue flash evokes a spike, like a note sounding when a piano key is pushed down. But a simultaneous flash of yellow light can block that spike. Consider the “musical score sheet” recorded from one such neuron as it is played with light. This ability to precisely control electrical activity in one or more neurons is unprecedented.