Caenorhabditis elegans exhibits a food-associated behavior that is modulated by the past cultivation temperature. Mutations in INS-1, the homolog of human insulin, caused the defect in this integrative behavior. Mutations in DAF-2/insulin receptor and AGE-1/phosphatidylinositol 3 (PI-3)-kinase partially suppressed the defect of ins-1 mutants, and a mutation in DAF-16, a forkhead-type transcriptional factor, caused a weak defect. In addition, mutations in the secretory protein HEN-1 showed synergistic effects with INS-1. Expression of AGE-1 in any of the three interneurons, AIY, AIZ, or RIA, rescued the defect characteristic of age-1 mutants. Calcium imaging revealed that starvation induced INS-1-mediated down-regulation of AIZ activity. Our results suggest that INS-1, in cooperation with HEN-1, antagonizes the DAF-2 insulin-like signaling pathway to modulate interneuron activity required for food-associated integrative behavior. The secreted peptide hormone insulin modulates neural plasticity. Insulin and insulin receptors are expressed in several regions of the rat brain (Havrankova et al. 1978a,b), insulin receptors localize to post-synapses (Abbott et al. 1999), and insulin can produce long-term depression (LTD) of synaptic transmission through endocytosis of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in rat hippocampal CA1 neurons (Man et al. 2000). In addition, Phosphatidylinositol 3 (PI-3)-kinase that functions in the insulin signaling pathway is thought to induce long-term potentiation (LTP) of synaptic transmission in the dentate gyrus of rat (Kelly and Lynch 2000). These alterations by proteins of the insulin signaling pathway may be involved in learning and memory, but what kind of behavior the insulin signaling pathway modulates has been largely unknown.The nematode Caenorhabditis elegans is well suited for the analysis of the molecular and cellular mechanisms underlying neural plasticity because of its accessible genetics, stereotyped behavioral responses, and its simple nervous system consisting of 302 neurons whose connections are entirely known (White et al. 1986). Recently, physiological analysis of the neural circuit in live worms has become possible by the use of cameleon, a genetically encodable calcium indicator, to measure Ca 2+ concentration changes (Miyawaki et al. 1997;Kimura et al. 2004).C. elegans exhibits thermotaxis, an integrative behavior in which well-fed animals in a thermal gradient are attracted to their cultivation temperature, whereas starved animals avoid it (Hedgecock and Russell 1975;Mohri et al. 2005;Rankin 2005). This food-associated behavioral plasticity, regarded the most complex behavior in C. elegans, is an ideal behavioral paradigm for comprehensive study of neural plasticity at the molecular, physiological, and behavioral levels. In this study, we show that in cooperation with a secreted protein HEN-1, an insulin homolog INS-1, and insulin-like signaling pathway modulate neuronal activity of interneurons to execute thermotaxis behavior in...

Animals modify behavioral outputs in response to environmental changes. C. elegans exhibits thermotaxis, where well-fed animals show attraction to their cultivation temperature on a thermal gradient without food. We show here that feeding-state-dependent modulation of thermotaxis is a powerful behavioral paradigm for elucidating the mechanism underlying neural plasticity, learning, and memory in higher animals. Starved experience alone could induce aversive response to cultivation temperature. Changing both cultivation temperature and feeding state simultaneously evoked transient attraction to or aversion to the previous cultivation temperature: recultivation of starved animals with food immediately induced attraction to the temperature associated with starvation, although the animals eventually exhibited thermotaxis to the new temperature associated with food. These results suggest that the change in feeding state quickly stimulates the switch between attraction and aversion for the temperature in memory and that the acquisition of new temperature memory establishes more slowly. We isolated aho (a bnormal h unger o rientation) mutants that are defective in starvation-induced cultivation-temperature avoidance. Some aho mutants responded normally to changes in feeding state with respect to locomotory activity, implying that the primary thermosensation followed by temperature memory formation remains normal and the modulatory aspect of thermotaxis is specifically impaired in these mutants.A NIMALS can modulate behavioral responses by susbehavioral genetic approach to dissecting the molecular tained training and retain memory for a certain mechanism of learning and memory because of its accestime. Learning and memory have been successfully insible genetics (Brenner 1974), its stereotyped behavvestigated using model organisms such as Aplysia, Droioral responses, and the ease of controlling experimensophila, and mice. Various learning paradigms have tal conditions in the laboratory. C. elegans is also ideal for been developed in each model and analyzed behavior-

Although recent studies have provided significant molecular insights into the establishment of neuronal polarity in vitro, evidence is lacking on the corresponding phenomena in vivo, including correct localization of synaptic components and the importance of this process for function of the nervous system as a whole. RIA interneurons act as a pivotal component of the neural circuit for thermotaxis behavior in the nematode Caenorhabditis elegans and provide a suitable model to investigate these issues, having a neurite clearly divided into pre-and post-synaptic regions. In a screen for thermotaxis mutants, we identified the gene ttx-7, which encodes myo-inositol monophosphatase (IMPase), an inositol-producing enzyme regarded as a bipolar disorder-relevant molecule for its lithium sensitivity. Here we show that mutations in ttx-7 cause defects in thermotaxis behavior and localization of synaptic proteins in RIA neurons in vivo. Both behavioral and localization defects in ttx-7 mutants were rescued by expression of IMPase in adults and by inositol application, and the same defects were mimicked by lithium treatment in wild-type animals. These results suggest that IMPase is required in central interneurons of the mature nervous system for correct localization of synaptic components and thus for normal behavior.[Keywords: C. elegans; thermotaxis behavior; protein localization; synapse; myo-inositol monophosphatase; lithium] Supplemental material is available at http://www.genesdev.org. Received April 19, 2006; revised version accepted October 23, 2006. Neurons are the most highly polarized animal cell type and are composed of several subcellular compartments, including axons, dendrites, and cell bodies, each of which has its own molecular and physiological characteristics. How these polarized compartments are established has been extensively investigated using cultured hippocampal neurons as a model system (Dotti and Banker 1987;Dotti et al. 1988). Recent studies have demonstrated that GSK-3␤ and small GTPase-mediated signaling pathways are critical in assigning axonal fate to the immature neurite in hippocampal neurons (Arimura and Kaibuchi 2005;Jiang et al. 2005). The established axonal compartment is physically separated from the cell body by a molecular diffusional barrier, which is at least partly responsible for maintaining the distinct character of these two compartments (Nakada et al. 2003). However, it remains to be determined whether these mechanisms are common to all neuronal types or other mechanisms exist as well. Furthermore, to understand the physiological importance of polarization and consequent subcellular heterogeneity such as localization of synaptic proteins, it is essential to evaluate how these subcellular phenomena in vivo correlate with the function of neurons and the nervous system as a whole.The nematode Caenorhabditis elegans has a simple nervous system that consists of 302 neurons, the synaptic connectivity of which has been described in its entirety by electron microscopy (White et al...

The nematode Caenorhabditis elegans exhibits a complex behavior called thermotaxis in response to temperature. This behavior is defined as a form of associative learning, in which temperature pairs with the presence or absence of food. Different interpretations have been drawn from the diverse results obtained by several groups, mainly because of the application of different methodologies for the analysis of thermotaxis. To clarify the discrepancies in behavioral observations and subsequent interpretations by different laboratories, we attempted to systematize several parameters to observe thermotaxis behavior as originally defined by Hedgecock and Russell in 1975. In this study, we show clearly how C. elegans can show a conditioned migration toward colder or warmer areas on a thermal gradient, given certain criteria necessary for the observation of thermotaxis. We thus propose to distinguish thermotaxis from other temperature-related behaviors, such as the warm avoidance response displayed at temperature gradients of 1• C/cm and steeper.