OptoMEG: Combining optogenetics and MEG for functional brain mapping
Understanding the relationship between local circuit activity and whole brain behavior is essential for developing a theory of information routing through the brain. Neural dynamics are difficult to study and interpret due to the complex nature of oscillations themselves and the wide range of spatial and temporal scales over which oscillatory relationships occur. Controlled modulation of local circuit activity while monitoring whole brain activity would allow for direct testing of the influence of upstream synchronous activity on downstream areas. Optogenetic techniques allow for precise control over the activity of anatomically and genetically defined populations, effectively placing whole populations, and their afferent projections, under analog control. Magnetic source imaging with MEG provides high temporal resolution and increasingly high spatial resolution across the whole brain. Using a novel integrative technique in a non-human primate model, we have combined magnetically inert optogenetic methods, local microelectrode depth recording, and whole brain MEG imaging. Stereotaxic MRI was used to target area CA3 of hippocampus and prefrontal area 8 in vervet monkeys. 4µl of AAV10-CaMKIIα-ChR2-eYFP was delivered stereotaxically along with a recording electrode and optical fiber to each location. Immediately after recovery pre-expression control stimulation experiments were conducted in order to evaluate the possibility of stimulation artifact prior to ChR2 expression. After a period of 6-10 weeks, stimulation protocols were again performed while conducting simultaneous MEG and LFP depth recordings. Optical stimulation protocols included single light pulses, train stimulation, and sinusoidal modulation at a variety of frequencies and intensities. MEG data were preprocessed and analyzed using Synthetic Aperture Magnetometry (SAM) from MISL. With this technique we were able to accurately localize the source of activation to hippocampus and cortex as well as identify distant responses to the stimulation. Different stimulation paradigms resulted in different patterns of downstream activation supporting established hypotheses regarding information routing through the whole brain; distant responders respected known anatomical and functional relationships. This series of experiments represents the first combination of optogenetics with MEG and demonstrates the utility of MEG in studying whole brain responses to local circuit modulation.