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.
Modern research strongly suggests that many of the most severe and disheartening mental illnesses (e.g., autism, schizophrenia, depression, obsessive-compulsive disorder) are disorders of the brain's connection patterns: they likely result from 'faulty circuits.' Yet so little is known about how detailed brain circuits lead to normal behavior- a prerequisite for understanding how the circuits can go awry - that a broad-based assault may be the most pro?table way to approach the disorders mentioned. We will be bringing an array of powerful techniques to bear on understanding how a relatively simple nervous system - that of the European medicinal leech - can select an appropriate behavior from several behaviors that multiple overlapping neuronal circuits produce, an ability that the healthy human brain excels at and that appears to be compromised in mental disease.
| Tomina, Yusuke; Wagenaar, Daniel A (2018) Dual-sided Voltage-sensitive Dye Imaging of Leech Ganglia. Bio Protoc 8: |
| Lehmkuhl, Andrew M; Muthusamy, Arunkumar; Wagenaar, Daniel A (2018) Responses to mechanically and visually cued water waves in the nervous system of the medicinal leech. J Exp Biol 221: |
| Tomina, Yusuke; Wagenaar, Daniel A (2017) A double-sided microscope to realize whole-ganglion imaging of membrane potential in the medicinal leech. Elife 6: |
