Genetics of nematode pharyngeal muscle excitability

我们在过去四年中最重要的成就可以简单地概括为：(1)我们有

Our most significant accomplishments in the last four years can be briefly summarized: (1) We have shown that worms alter their behavior depending on food quality. They seek high-quality food by altering their locomotion. This behavior is plastic, in that it is modified by past experience and hunger. (2) We have worked out a molecular pathway that is induced by starvation, and that leads to changed feeding behavior. We call this the hunger pathway, operationally defining hunger as an internal state that satisfies two criteria: ) it is brought on by starvation, and (2) it causes an increase in feeding and food-seeking behavior. (3) We lave found a new behavior that resembles satiety in vertebrates. When fed an excess of high-quality food, worms (apparently) become full: they stop eating, slow down, and appear to fall asleep. Together, these discoveries have given us insight into a broad question of great significance, whose existence we were barely even aware of 4 years ago: how is appetite controlled? There are few universal truths in biology, but the following is a candidate: All organisms must adapt to the quality and quantity of food available in their environment. Human responses to food evolved in an environment where high-calorie food was scarce and precious. In our novel, nutritionally rich environment, improper control of appetite contributes to diseases from anorexia to the current epidemic of obesity. We propose, in the years of extended funding, to continue our investigation of this new problem of appetite ;ontrol. Our specific aims are: Aim 1: Upstream mechanisms in hunger signaling. Aim 2: Downstream effects of hunger signaling. Aims 1 and 2 focus on hunger signaling. The core hunger signaling pathway in pharyngeal muscle extends from the muscarinic acetylcholine receptor GAR-3 to the MAP kinase MPK-1. We call this a hunger pathway because (1) it is activated by starvation, and (2) it has physiological and behavioral effects that allow the animals to cope. This raises two obvious questions: Aim 1:What is upstream of the muscarinic receptor? How is the pathway activated by starvation? Aim 2: What is downstream of MPK-1? How does activation of the pathway change physiology and behavior? Aim 3: Cellular and molecular mechanisms of food preference. Aim 3 will focus on food preference. Here we will focus on a single question: by what cellular and molecular mechanisms is high-quality food distinguished from low? A genetic screen will identify genes necessary for food preference. Calcium imaging will test the hypothesis that specific interneurons in the locomotory circuit respond to food quality.