Molecular and physiological basis of learning and memory in the neural circuit of behavior.

   Animals are capable of sensing and memorizing a large repertoire of environmental stimuli to execute appropriate behaviors. Our laboratory utilizes C. elegans, a small soil nematode species, as a model to understand the molecular and neural mechanisms of animal behavior. The neural circuitry controls animal behavior. In C. elegans, mechanisms underlying behavioral control can be studied by integrating analyses at the molecular (genes), cellular (neurons), neural circuit (neuronal wiring), and individual animal (behavior) levels. Our laboratory is focused on the behavioral responses of C. elegans to temperature. The aims of our research are mainly twofold: elucidation of the mechanisms by which animals (1) sense temperature and (2) memorize temperature. To study these questions, we are analyzing thermotaxis behavior. After normal cultivation with food at a certain temperature, such as 20 degree, and placement on a temperature gradient ranging from 17 to 25 degree, C. elegans migrates to the cultivation temperature (20 degree). We have previously determined the neural circuit essential for this thermotaxis behavior. We have recently isolated several genes required for thermotaxis and have shown that some of these genes are also important for smell and vision in humans, which led us to propose a molecular model for thermosensation. We further demonstrated that thermotaxis is the behavioral outcome of associative learning between temperature and feeding state. We have identified genes specifically required for the memory-controlled aspect of thermotaxis.

   How do genes acting in the neural circuitry generate behavior? To address this important physiological issue, we monitored the activities of the component neurons in the thermotaxis neural circuit in live animals. We have shown that a thermosensory neuron is upregulated by the temperature change. We are conducting experiments to monitor physiological changes of interneurons upon temperature memory formation and association between temperature and feeding state. In addition, we have started to apply systems biology on the thermotaxis neural circuit and its behavior. Toward this end, we are now challenging to perform mathematical modeling of the neural circuit activities and thermotaxis behavior.

(1) Bargmann, C.I. and Mori, I. (1997) Chemotaxis and thermotaxis. In C. elegans II (ed. D.L. Riddle et al.), pp.717-737. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York

(2) Mori, I. and Ohshima, Y. (1997) Molecular neurogenetics ofchemotaxis and thermotaxis in the nematode Caenorhabditis elegans. BioEssays 19: 1055-1064.

(3) Mori, I. (1999) Genetics of chemotaxis and thermotaxis in the nematode Caenorhabditis elegans. Ann. Rev. Genet. 33, 399-422.

2. ACADEMIC PAPERS(Peel-reviewed papers)

(1) Mori, I. and Ohshima, Y. (1995) Neural regulationof thermotaxis in Caenorhabditis elegans. Nature 376: 344-348.

(2)Komatsu. H., Mori, I., Rhee, J.-S., Akaike, N. and Ohshima, Y. (1996) Mutations in a cyclic nucleotide-gated channel lead to abnormal thermosensation and chemosensation in C. elegans. Neuron 17: 707-718.

(3) Hobert, O., Mori, I., Yamashita, Y., Honda, H., Ohshima, Y. Liu, Y. and Ruvkun, G. (1997) Regulation of interneuron function in the C. elegans thermoregulatory pathway by the ttx-3 homeobox gene. Neuron 19: 345- 357.

(4) Coburn, C.M., Mori, I., Ohshima, Y. and Bargmann, C.I. (1998) A cyclic nucleotide-gated channel inhibits sensory axon outgrouwh in larval and adult C. elegans: a dinstinct pathway for maintenance of sensory axon structure. Development 125: 249-258.

(5) Komatsu, H., Jin, Y.-H., L'Etoile, N., Mori, I., Bargmann, C.I., Akaike, N. and Ohshima, Y. (1999) Functional reconsitution of alpha and beta subunits of the C. elegans cyclic nucleotide-gated channels. Brain Research 821: 160-168.

(6) Gomez, M., De Castro, E., Guarin, E., Sasakura, H., Kuhara, A., Mori, I., Bartfai, T., Bargmann, C. I. and Nef, P. (2001) Ca²⁺ signaling via the neuronal calcium sensor-1 regulates associative learning and memory in C. elegans. Neuron 30: 241-248.

(7) Satterlee, J. S., Sasakura, H., Kuhara, A., Berkeley, M., Mori, I. and Sengupta, P. (2001) Specification of thermosensory neuron fate in C. elegans requires ttx-1, a Homolog of otd/Otx. Neuron 31: 943-956.

(8) Ishihara, I., Iino, Y., Mohri, A., Mori, I., Gengyo-Ando, K., Mitani, S. and Katsura, I. (2002) HEN-1, a secretory protein with a LDL receptor motif, regulates sensory integration and learning in Caenorhabditis elegans. Cell 109, 639-649.

(9) Kuhara, A., Inada, H., Katsura, I., and Mori, I. (2002) Negative regulation and gain control of sensory neurons by the C. elegans calcineurin TAX-6. Neuron 33: 751-763.

(10) Shimozono, S., Fukano, T., Kimura, K. D., Mori, I. Kirino, Y. and Miyawaki, A. (2004) Slow Ca2+ dynamics in pharyngeal muscles in Caenorhabditis elegans during fast pumping. EMBO Rep. 5, 521-526.

(11) Kimura, K. D., Miyawaki, A., Matsumoto, K. and Mori, I. (2004) The C. elegans Thermosensory Neuron AFD Responds to Warming. Curr Biol 14: 1291-1295.

(12) Okochi, Y., Kimura, K. D., Ohta, A. and Mori, I. (2005) Diverse regulation of sensory signaling by nPKC-epsilon/eta TTX-4 in the nematode C. elegans. EMBO J. 24: 2127-2137.

(13) Sasakura, H., Inada, H., Kuhara, A., Fusaoka, E., Takemoto, D., Takeuchi, K. and Mori, I. (2005) Maintenance of neuronal positions in organized ganglia by SAX-7, a Caenorhabditis elegans homologue of L1. EMBO J. 24: 1477-1488.

(14) Mohri, A., Kodama, E., Kimura, K. D., Koike, M., Mizuno, T. and Mori, I. (2005)  Genetic Control of Temperature Preference in the Nematode Caenorhabditis elegans. Genetics 169: 1437-1450.

(15) Inada,H., Ito,H., Satterlee, J., Sengupta, P., Matsumoto, K. and Mori, I. (2006) Identification of guanylyl cyclases that function in thermosensory neurons of Caenorhabditis elegans. Genetics.172:2239-2252.

(16) Ito, H.*, Inada, H.* and Mori, I. (*equally contributed) (2006) Quantitative analysis of thermotaxis in the nematode Caenorhabditis elegans.  J Neurosci Meth.154:45-52.

(17) Kuhara, A. and Mori, I. (2006) Molecular physiology of the neural circuit for calcineurin-dependent associative learning in Caenorhabditis elegans. J Neurosci, 26:9355-9364.

(18) Kodama, E., Kuhara, A., Mohri-Shiomi, A., Kimura, K. D., Okumura, M., Tomioka, M., Iino, Y., and Mori, I. (2006)
Insulin-like signaling and the neural circuit for integrative behavior in C. elegans. Genes Dev, 20: 2955-2960.

(19) Tanizawa, Y., Kuhara, A., Inada, H., Kodama, E., Mizuno, T., and Mori, I. (2006) Inositol Monophosphatase regulates localization of synaptic components and behavior in the mature nervous system of C. elegans.
Genes Dev, 20:3296-3310.

(20) Mori, I., Sasakura, H. and Kuhara, A.(2008) Worm thermotaxis: a model for analyging thermosensation and neural plasticity. Curr. opinion. Neurobiol. 17, 712-719.

3. Others(Not Peer-reviewed papers)　

(1) Mori, I. (1991) Genetic and molecular studies on thermotaxis of the nematode Caenorhabditis elegans. Research projects in reviews, Nissan Science Foundation 14: 257-258.