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Significance Physiological stress triggers avoidance behavior, allowing the animals to stay away from potential threats and optimize their chance of survival. Mitochondrial disruption, a common physiological stress in diverse species, induces the nematode Caenorhabditis elegans to avoid non-pathogenic bacteria through a serotonergic neuronal circuit. We find that distinct neurons, communicated through serotonin and a specific serotonin receptor, are required for the formation and retrieval of this learned aversive behavior. This learned avoidance behavior is associated with increased serotonin synthesis, altered neuronal response property, and reprogramming of locomotion patterns. The circuit and neuromodulatory mechanisms described here offer important insights for stress-induced avoidance behavior.

Self-avoidance is a conserved mechanism that prevents crossover between sister dendrites from the same neuron, ensuring proper functioning of the neuronal circuits. Several adhesion molecules are known to be important for dendrite self-avoidance, but the underlying molecular mechanisms are incompletely defined. Here, we show that FMI-1/Flamingo, an atypical cadherin, is required autonomously for self-avoidance in the multidendritic PVD neuron of Caenorhabditis elegans. The fmi-1 mutant shows increased crossover between sister PVD dendrites. Our genetic analysis suggests that FMI-1 promotes transient F-actin assembly at the tips of contacting sister dendrites to facilitate their efficient retraction during self-avoidance events, probably by interacting with WSP-1/N-WASP. Mutations of vang-1, which encodes the planar cell polarity protein Vangl2 previously shown to inhibit F-actin assembly, suppress self-avoidance defects of the fmi-1 mutant. FMI-1 downregulates VANG-1 levels probably through forming protein complexes. Our study identifies molecular links between Flamingo and the F-actin cytoskeleton that facilitate efficient dendrite self-avoidance.

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24Biomolecules that respond to different external stimuli enable the remote control of genetically 25 modified cells. Chemogenetics and optogenetics, two tools that can control cellular activities 26 via synthetic chemicals or photons, respectively, have been widely used to elucidate underlying 27 physiological processes. These methods are, however, very invasive, have poor penetrability, 28 or low spatiotemporal precision, attributes that hinder their use in therapeutic applications. We 29 report herein a sonogenetic approach that can manipulate target cell activities by focused 30 ultrasound stimulation. This system requires an ultrasound-responsive protein derived from an 31 engineered auditory-sensing protein prestin. Heterogeneous expression of mouse prestin 32 containing two parallel amino acid substitutions, N7T and N308S, that frequently exist in 33 prestins from echolocating species endowed transfected mammalian cells with the ability to 34 sense ultrasound. An ultrasound pulse of low frequency and low pressure efficiently evoked 35 cellular calcium responses after transfecting with prestin(N7T, N308S). Moreover, pulsed 36 ultrasound can also non-invasively stimulate target neurons expressing prestin(N7T, N308S) 37 in deep regions of mice brains. Our study delineates how an engineered auditory-sensing 38 protein can cause mammalian cells to sense ultrasound stimulation. Moreover, owing to the 39 great penetration of low-frequency ultrasound (~400 mm in depth), our sonogenetic tools will 40 serve as new strategies for non-invasive therapy in deep tissues of large animals like primates. 41 42 43 44 45 46