| Insulin signaling is highly conserved across animals, and is known for its ubiquitous function in all aspects of animal physiology. Despite its relatively well-studied role in metabolism and energy expenditure, how it is involved in learning and memory remains a mystery, due to the complex nature of the nervous system. In this thesis, I have used C. elegans, a tractable model organism with a sophisticated behavioral repertoire, to investigate molecular and cellular mechanisms of insulin signaling in learning. At the molecular level, I show that two insulin-like ligands, INS-6 and INS-7, play antagonistic roles in C. elegans olfactory learning. INS-6 enhances learning ability, whereas INS-7 dampens it. Their presence and interaction regulates the overall strength and intensity of insulin signaling, resulting in a fine-tuning of behavioral plasticity. At the circuit level, I identified a small circuit for olfactory learning behavior involving both sensory neurons and interneurons. The circuit is regulated by varying expression levels of INS-6 and INS-7 and is responsible for the physiological response of downstream neurons. Together, this thesis elucidates the molecular and circuit mechanism of insulin signaling in learning and behavioral plasticity by focusing on a specific set of insulin interaction and function. The insulin gene superfamily is often divergent in sequence and function for many species. Despite the magnitude of divergence, the insulin gene family maintains a certain level of redundancy as well. A fine balance between gene divergence and redundancy, diversity and specificity is expected, observed and yet poorly understood. This question leads to my second project, in which I have collaborated with multiple labs to investigate the function of 33 insulin-like ligands. I profiled the function of 33 insulin-like ligands in the innate immune response by measuring pathogen resistance of C. elegans being exposed to a microbial pathogen, Pseudomonas aeruginosa PA14. Together with observations made in other labs, it is clear that the insulin gene family encodes a high degree of functional specificity. This systemic profiling of insulin gene function reveals complex relationships between members of the family. |
