The neocortex is an evolutionarily new part of the brain unique to mammals and is responsible for high level sensation, movement and cognition. It wouldn't be fair to summarize in a sentence or two what cortex "does," but it is clear that it is an important part of the brain. Korbinian Brodmann famously divided the human cortex into about 50 areas based on histology of the six cortical layers in different parts of the brain; Brodmann's areas are still used today because their functions follow their histological structure. While cortical areas have largely stereotyped wiring patterns, some connectivity “motifs” are thought to be area-specific, varying based on the type of input the area receives. It is unknown whether the type of input (i.e. statistics of incoming activity that vary with types of sensory stimuli) to a given cortical area determines the types of connectivity motifs present in that region. And while classical cortical “rewiring”experiments from Mriganka Sur’s lab have shown that primary sensory cortices are somewhat tolerant to process foreign inputs, it is not clear to what extent those circuits constitute basic computational units or if foreign inputs cause reorganization of connections within the circuit.
Opto-fMRI
Opto-fMRI
fMRI has traditionally been used for mapping the brain and correlating brain function with specific structures. The method has become a sort of laughing-stock within the electrophysiological community because of the countless studies that proclaim region A to be responsible for function B. A typical blunder can go like this: "Increased activation of the amygdala during a fear conditioning task suggests that the amygdala is the brain's fear center." To be fair, the method is still very useful and serious scientists don't fall into this fallacy as much as the popular media does. Some outstanding questions are what the measured signal (blood oxygenation level; BOLD) actually means for neural activity; whether it's possible to disambiguate excitation from inhibition; how activation in one region affects connected regions; and what the causal relationships among activated regions are. To address the last two of these, Ed Boyden and colleagues at MIT used a combination of optogenetics and fMRI (Opto-fMRI) in awake mice. The idea is that if they can change the dynamics of a defined population of cells in a localized and fast way (they infected pyramidal cells in mouse somatosensory cortex with ChR2), the network effects of that activation would be revealed by fMRI. In this way, they validate the network effects in both technologies. One limitation that's still inherent to fMRI is the slow temporal resolution - while optogenetic stimulation changes membrane potential with millisecond-resolution, fMRI's hemodynamic response is much slower. Perhaps other imaging methods like multiphoton imaging may be used in the future to dissect large-scale circuits in awake animals.
Optogenetics to Cure Alzheimer's?
Preparing for SfN 2011, I have to give a shout-out to one of the coolest emerging technologies in neuroscience, optogenetics. Optogenetics, as everyone no doubt knows by now, is a method that allows researchers to control the electrical activity of neurons using light. Scientists infect certain types of neurons with an algae transmembrane channel protein that allows the flow of ions into a cell when light of preferred wavelength shines upon it. The method has been described well elsewhere (Steve Ramirez waxes poetic about it on the Mind the Gap Junction blog). Optogenetics is an amazing method for many reasons, but mainly because by allowing us to directly activate or silence neurons, it makes it possible to establish causal relationships in neural circuits: if neuron A is hyperactive, the mouse runs around in circles; if A is silenced, perhaps the mouse is unable to run in circles; therefore, activity in neuron A causes the mouse to run in circles. This is important because traditional electrophysiological methods allow us to only record activity without manipulating it directly (stimulating electrodes are rather crude spatially), and the methods that did allow us to manipulate activity (i.e. pharmacology or stimulating electrodes) have a myriad of effects that make precise causes of behavior unclear (i.e. does TTX act only on sodium channels? Which types? etc).
As optogenetics becomes more and more refined and widespread, I can't help to wonder what it will do for the most prevalent of neurological diseases. Will this method cure Alzheimer's? How about Parkinson's? Optogenetics promises to show us circuit-level interactions among neurons and perhaps even to nail down the network effects of particular diseases. But if we're looking to find cures for diseases instead of just fixes, we ought to not forget our molecular biologists and maybe even geneticists. That's not to say that treatments for neurological diseases are worthless! There are, after all, no cures for any brain diseases so far - so anything will be useful. With all this enthusiasm over optogenetics, we have to be honest about its capabilities and limitations.