Non-Canonical Axonal Insulin Receptor Signaling Drives Aversive Olfactory Learning

<p>Animals rely on their flexible nervous systems to learn to navigate the changing environment around them. One important function of the nervous system is to form associative memories. A simple model of associative learning is provided by nematode C. elegans, which can form memories of different types of odor stimuli through its simple yet sophisticated nervous system. C. elegans uses its sensory neurons to detect and navigate towards the odors of its food source - edible bacteria. Thus, it is crucial for worms to form memories between odors and availably of food. The volatile chemical butanone is a common product of bacterial metabolism, and therefore a bacterial odor that is attractive to worms. However, exposing C. elegans to butanone vapor while depriving them of food can suppress this attraction. C. elegans senses butanone with its AWCON neuron, and the information is further integrated before its delivery onto a network of interneurons, where it is processed for control of navigation. In my thesis, I systematically characterize aversive learning induced by pairing butanone odor with food deprivation. I employ a wide variety of experiments to understand C. elegans' changes in molecular pathways, neuronal dynamics, and behavior output mechanics during aversive learning. In Chapter 1, I introduce how studying the neuronal and genetic mechanism of learning in C. elegans can contribute to the understanding of our brains and diseases of the brain. I briefly describe how insulin and insulin-like growth factor pathways regulate learning in humans and other mammals. In Chapter 2, I explore and refine the stimulation conditions that decrease or enhance C. elegans's attraction to butanone. I separate the effect of odor exposure alone (desensitization) and odor-starvation paired conditioning (aversive learning) using a comprehensive behavior testing approach. I conduct a candidate gene screen for aversive learning defects, and identify the C. elegans homolog of the Insulin Receptor Substrate (IRS) (ist-1) as a gene required for aversive odor learning. I also demonstrate odor- and cell-specific functions of ist-1. In Chapter 3, I characterize insulin signaling in the aversive learning process. I describe the cell-specific activity of an axonally-localized isoform of the insulin receptor DAF-2 in aversive learning. I perform epistasis studies of ist-1 with other members of the insulin signaling pathway to ask how they regulate aversive learning together. In Chapter 4, I characterize neuronal mechanisms involved in odor detection and learning through AWCON cell body calcium imaging and pHluorin imaging of synaptic glutamate release, and ask how ist-1 modifies these mechanisms during learning. I show that these molecular and neuronal mechanisms result in behavior changes during biased random walk chemotaxis.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Thesis

Year

2021

Author dc:creator

• Cheng, Du

Contributors dc:contributor

• Cori Bargmann

• associative learning
• C. elegans
• butanone
• aversive conditioning
• insulin signaling
• ist-1 gene
• Life Sciences

Repository record dc:identifier

https://digitalcommons.rockefeller.edu/student_theses_and_dissertations/637

OAI identifier oai:identifier

oai:digitalcommons.rockefeller.edu:student_theses_and_dissertations-1643