A major challenge in neuroscience is to reliably activate individual neurons, particularly those in deeper brain regions. Current optogenetic approaches require invasive surgical procedures to deliver light of specific wavelengths to target cells in order to activate or silence them. Here, we demonstrate the use of low-pressure ultrasound as a non-invasive trigger to activate specific ultrasonically-sensitized neurons in the nematode, Caenorhabditis elegans. We first show that wild-type animals are insensitive to low pressure ultrasound and require gas-filled microbubbles to transduce the ultrasound wave. We find that neuron-specific misexpression of TRP-4, the pore-forming subunit of a mechanotransduction channel, sensitizes neurons to ultrasound stimulus resulting in motor outputs. Furthermore, we use this approach to manipulate the function of sensory neurons and interneurons and identify a role for the PVD sensory neurons in modifying locomotory behaviors. We suggest this method can be broadly applied to manipulate cellular functions in vivo.
Summary The ability to evaluate variability in the environment is vital for making optimal behavioral decisions. Here we show that Caenorhabditis elegans evaluates variability in its food environment and then modifies its future behavior accordingly. We derived a behavioral model that reveals a critical period over which information about the food environment is acquired and predicts future search behavior. We identified a pair of high-threshold sensory neurons that encode variability in food concentration and downstream dopamine-dependent circuitry that generates appropriate search behavior upon removal from food. Further, we show that CREB is required in a subset of interneurons and determines the timescale over which the variability is integrated. Interestingly, the variability circuit is a subset of a larger circuit driving search behavior, showing that learning directly modifies the very same neurons driving behavior. Our study reveals how a neural circuit decodes environmental variability to generate contextually appropriate decisions.
Animals respond to predators by altering their behavior and physiological states, but the underlying signaling mechanisms are poorly understood. Using the interactions between Caenorhabditis elegans and its predator, Pristionchus pacificus, we show that neuronal perception by C. elegans of a predator-specific molecular signature induces instantaneous escape behavior and a prolonged reduction in oviposition. Chemical analysis revealed this predator-specific signature to consist of a class of sulfolipids, produced by a biochemical pathway required for developing predacious behavior and specifically induced by starvation. These sulfolipids are detected by four pairs of C. elegans amphid sensory neurons that act redundantly and recruit cyclic nucleotide-gated (CNG) or transient receptor potential (TRP) channels to drive both escape and reduced oviposition. Functional homology of the delineated signaling pathways and abolishment of predator-evoked C. elegans responses by the anti-anxiety drug sertraline suggests a likely conserved or convergent strategy for managing predator threats.
Ultrasound is an ideal modality to stimulate neurons due to its ability to focus through deep tissue. To facilitate the selective ultrasound activation of neurons within a dense network, we have developed a new method called sonogenetics where we genetically sensitize individual neurons to respond to the mechanical deformations created by an ultrasound pulse. This was done by misexpressing the TRP4 mechanotransduction ion channel in select neurons. As a model system, we used Caenorhabditis elegans nematodes which were allowed to freely move on the surface of an agar gel. We found that ultrasound alone did not create enough mechanical deformation at the surface of the agar to activate the TRP4 channels. To overcome this challenge, we introduced stabilized microbubbles to the system by plating them on the gel surface where they naturally surrounded the worms. The interaction between the microbubbles and the ultrasound created mechanical deformations that propagated into the body of the worm and successfully activated the expressed TRP4 causing subsequent neural activation. Activation was confirmed using calcium dependent fluorescent dyes and by quantifying whole worm behavioral changes. This technique can be a valuable tool for future applications in mammalian neural systems aimed at understanding complex neural circuits.
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