The small size, fast generation time and genetic tractability of C. elegans in combination with its use as a model organism for human diseases have allowed researchers to perform a variety of high-throughput (HT) assays to study human diseases and reveal potential drug treatments. Well-established protocols for anatomical imaging, protein expression, and behavioral profiling exist and are widely used for phenotyping worms in HT experiments. However, when modeling neurological diseases such as Parkinson’s disease (PD) and Amyotrophic Lateral Sclerosis (ALS), researchers need a reliable measure of neural activity in order to accurately phenotype the disease state of worms. Typical electrophysiology techniques require laborious dissections followed by micropipette patch-clamp measurements. This methodology alters the in vivo concentration of signaling molecules and most notably is low-throughput, limiting researchers to only a handful of experiments per day. As a result, C. elegans studies rarely reveal information about the physiological effects of neuroprotective drugs or how the genetic pathways involved in diseases modulate the electrical activity of the nervous system. A HT method to record electrophysiology would open the door to powerful new phenotyping methods that capture subtle differences in neural activity as affected by diseases. To circumvent the difficulty of conventional methods and to create a scalable platform for electrophysiology, we invented a microfabricated device based on suspended nano-electrodes (SNEs) integrated onto a microfluidic platform. Using microfluidics for manipulation, we discovered that when worms are tightly immobilized against SNEs, we record electrophysiological activity at the body wall neuromuscular junction with animals remaining intact and viable for at least several hours. Importantly, this platform allows for phenotyping based on action potential waveforms, spike statistics and power spectral densities. Using these metrics, we have made the first phenotypic profiles of PD and ALS models based on electrophysiology and shown a partial rescue of normal activity in PD models after pharmacological treatment. These results along with the scalability of SNE technology represent a new paradigm in the use of C. elegans for the study of neurological diseases in which behavioral, anatomical and electrophysiological data can all be combined for high-dimensional phenotyping in HT drug and genetic screening experiments.
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