Search

Physiological stress induces aversive memory formation and profoundly impacts animal behavior. In C. elegans, concurrent mitochondrial disruption induces aversion to the bacteria that the animal inherently prefers, offering an experimental paradigm for studying the neural basis of aversive memory. We find that, under mitochondrial stress, octopamine secreted from the RIC modulatory neuron targets the AIY interneuron through the SER-6 receptor to trigger learned bacterial aversion. RIC responds to systemic mitochondrial stress by increasing octopamine synthesis and acts in the formation of aversive memory. AIY integrates sensory information, acts downstream of RIC, and is important for the retrieval of aversive memory. Systemic mitochondrial dysfunction induces RIC responses to bacterial cues that parallel stress induction, suggesting that physiological stress activates latent communication between RIC and the sensory neurons. These findings provide insights into the circuit and neuromodulatory mechanisms underlying stress-induced aversive memory.

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.

Physiological stress triggers aversive learning that profoundly alters animal behavior. Systemic mitochondrial disruption induces avoidance of C. elegans to non-pathogenic food bacteria. Mutations in cat-2 and dat-1, which control dopamine synthesis and reuptake, respectively, impair this learned bacterial avoidance, suggesting that dopaminergic modulation is essential. Cell-specific rescue experiments indicate that dopamine likely acts from the CEP and ADE neurons to regulate learned bacterial avoidance. We find that mutations in multiple dopamine receptor genes, including dop-1, dop-2 and dop-3, reduced learned bacterial avoidance. Our work reveals a role for dopamine signaling in C. elegans learned avoidance behavior induced by mitochondrial stress.

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 C. 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, likely 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 level likely through forming protein complexes. Our study identifies molecular links between Flamingo and the F-actin cytoskeleton for efficient dendrite self-avoidance.

Signaling that instructs the migration of neurons needs to be tightly regulated to ensure precise positioning of neurons and subsequent wiring of the neuronal circuits. Wnt-Frizzled signaling controls neuronal migration in metazoans, in addition to many other aspects of neural development. We show that Caenorhabditis elegans VANG-1/ Vangl2, a membrane protein that acts in the planar cell polarity (PCP) pathway, antagonizes Wnt signaling by facilitating endocytosis of the Frizzled receptors. Mutations of vang-1 suppress migration defects of multiple classes of neurons in the Frizzled mutants, and overexpression of vang-1 causes neuronal migration defects similar to those of the Frizzled mutants. Our genetic experiments suggest that VANG-1 facilitates Frizzled endocytosis through β-arrestin2. Coimmunoprecipitation experiments indicate that Frizzled proteins and VANG-1 form a complex, and this physical interaction requires the Frizzled cysteine-rich domain (CRD). Our work reveals a novel mechanism mediated by the PCP protein VANG-1 that downregulates Wnt signaling through Frizzled endocytosis.

Chinese herbal medicines (CHMs) have been used to treat human diseases for thousands of years. Among them, Ginkgo biloba is reported to be beneficial to the nervous system and a potential treatment of neurological disorders. Since the presence of adult neural stem cells (NSCs) brings hope that the brain may heal itself, whether the effect of Ginkgo biloba is on NSCs remains elusive. In this study, we found that Ginkgo biloba extract (GBE) and one of its main ingredients, ginkgolide B (GB) promoted cell cycle exit and neuronal differentiation in NSCs derived from the postnatal subventricular zone (SVZ) of the mouse lateral ventricle. Furthermore, the administration of GB increased the nuclear level of β-catenin and activated the canonical Wnt pathway. Knockdown of β-catenin blocked the neurogenic effect of GB, suggesting that GB promotes neuronal differentiation through the Wnt/β-catenin pathway. Thus, our data provide a potential mechanism underlying the therapeutic effect of GBE or GB on brain injuries and neurodegenerative disorders.

Summary Self-avoidance allows sister dendrites from the same neuron to form non-redundant coverage of the sensory territory and is important for neural circuitry functions. Here, we report an unexpected, cell-autonomous role of the Wnt-secretory factor MIG-14/Wntless in mediating dendrite self-avoidance in the C. elegans multidendritic PVD neurons. Similar findings in Drosophila suggest that this novel function of Wntless is conserved. The mig-14 mutant shows defects in dendrite self-avoidance, and ectopic MIG-14 expression triggers dendrite repulsion. Functions of dendrite self-avoidance and Wnt secretion could be mapped to distinct MIG-14 domains, indicating that these two functions of MIG-14 are genetically separable, consistent with lack of self-avoidance defects in the Wnt mutants. We further demonstrate that MIG-14 engages Wiskott-Aldrich syndrome protein (WASP)-dependent actin assembly to regulate dendrite self-avoidance. Our work expands the repertoire of self-avoidance molecules and uncovers a previously unknown, Wnt-independent function of MIG-14/Wntless.

Neurons remodel their connectivity in response to various insults, including microtubule disruption. How neurons sense microtubule disassembly and mount remodeling responses by altering genetic programs in the soma are not well defined. Here we show that in response to microtubule disassembly, the Caenorhabditis elegans PLM neuron remodels by retracting its synaptic branch and overextending the primary neurite. This remodeling required RHGF-1, a PDZ-Rho guanine nucleotide exchange factor (PDZ-RhoGEF) that was associated with and inhibited by microtubules. Independent of the myosin light chain activation, RHGF-1 acted through Rho-dependent kinase LET-502/ROCK and activated a conserved, retrograde DLK-1 MAPK (DLK-1/dual leucine zipper kinase) pathway, which triggered synaptic branch retraction and overgrowth of the PLM neurite in a dose-dependent manner. Our data represent a neuronal remodeling paradigm during development that reshapes the neural circuit by the coordinated removal of the dysfunctional synaptic branch compartment and compensatory extension of the primary neurite.