Daniel A. Wagenaar - US grants

? DESCRIPTION (provided by applicant): How brain activity can lead to complex and ?exible behavioral outputs has fascinated neuroscientists and philosophers alike. There is mounting evidence that complex behaviors result from the activity of a multitude of simpler (sometimes competing) circuits. Yet, our understanding of even the simplest circuits remains spotty, in part because available technology has limited researchers to studying only one or a few aspects of a circuit at a time. We stand at the cusp of a revolution in recording and imaging technology that will ultimately allow us to investigate comprehensively how the fundamental biological building blocks of the human brain are constructed and ?t together. Even now, the limitations mentioned no longer apply to certain less complex, more experimentally approachable brains. These provide attractive stepping stones for understanding our own complex brain. The relatively simple nervous system of the European medicinal leech will be used to develop insights about how the activity of all the cells in a nervous system together produce individual behaviors from overlapping functional networks, a phenomenon that - at a much larger scale and undoubtedly with many complexities added - is also crucial to human brain function. Three types of experiments will be performed: Record the activity of all the neurons in a ganglion - the unit of activity in this animal's brain - using high-resolution voltage-sensitive dye imaging, as it perfors four different behaviors - swimming, crawling, local bending, and shortening. Use electron microscopy to reconstruct the full connectivity pattern - the connectome - of the same ganglion that was imaged. Use electrophysiology to add functional signi?cance to the anatomical connectome. Obtaining a simultaneous activity record of all the individual neurons in a ganglion as it generates several behaviors will be a ?rst. Combining this record with the reconstructed connectome of that very same ganglion will establish a data set with unprecedented potential for advancing our understanding of the link between neuronal connectivity and behavior. A particular focus will be on neurons and synaptic connections that span multiple behavioral circuits, to determine their roles in selecting behaviors. This project will generate huge amounts of data on circuit anatomy and neuronal activity. These data will be made generally available, so that other laboratories can generate and test hypotheses of their own on function and connectivity of leech neural circuits. Many aspects of the dynamics that the leech nervous system uses to select and perform behaviors appear to be similar to the mechanisms used by more complex brains. Accordingly, the value of the hypotheses that we and other users of our data will generate may extend far beyond the leech to distant branches of the taxonomic tree including our own.

ABSTRACT Towards noninvasive magnetic control of cells ? a global search for magnetoreceptors If biological cells could be controlled using magnetic fields, this would enable unprecedented approaches to basic biology and medicine. Ideally one would want a genetic tool that can render arbitrary cells magnetically sensitive, a goal now known as ?magnetogenetics?. Several attempts to accomplish this by de novo bioengineering have failed, mainly because magnetic fields interact only weakly with biological molecules. At the same time we know that certain animal species have the remarkable ability to sense the Earth's magnetic field and to use this information for orientation and navigation. Thus there must exist nerve cells with the mechanism to transduce even weak magnetic fields: the magnetoreceptors. If one could find those receptor neurons, they would reveal a cellular pathway that could be used for magnetic control. Remarkably the identity and mechanism of magnetoreceptor neurons is still unknown. The approach proposed here is to first search for neural signals anywhere in the brain that respond to magnetic stimuli. Based on those signals one can engage a magnetic scanning method to localize where the magnetic responses originate. Ultimately this will lead to the receptor cells. The first and essential step is to find an unambiguous neuronal response to magnetic fields in any species. The research presented here will accomplish this through a collective science project that will coordinate many laboratories for a short duration. These days scores of research groups are engaged in high-throughput neuroscience pursuing a broad range of questions in diverse species. Revolutionary improvements in the tools of neurophysiology enable experiments that routinely record signals from hundreds to thousands of neurons at a time. The project will transiently engage about 50 of these laboratories in a broad unbiased search for magnetoreceptors. Building on personal contacts the PI has already secured agreement from an illustrious list of pilot collaborators to offer experimental time and share data. The Caltech team will construct electromagnetic stimulators that produce a defined magnetic field and ship these to each partner lab. The device can be added easily to an ongoing experiment, and a mere 20 minutes of recording will reveal whether any of the neurons under study carry magnetic signals. The team will collect all the resulting data and analyze them for magnetic responses. A positive finding will immediately be subject to independent replication. By the end of the two-year period the project is expected to screen several million neurons in many different animal species and brain areas for magnetic responses, at least a 100-fold increase over the cumulative effort to date. If this exploratory research program yields magnetoreceptors in any species, that will set the stage for future work that unlocks their biophysical mechanisms and ultimately realizes the dream of magnetogenetics.