We are interested in how, given a set of environmental cues, an animal with a specific history and internal state will respond in a stereotyped manner. The brain and how it interacts with the body is complex and is largely unknown. Because of this, we favor unbiased phenotypic and molecular screens that can reveal undiscovered genetic and neural circuit bases for behavior.
The fruit fly Drosophila melanogaster has a relatively simple nervous system that is capable of coding for sophisticated behavioral responses. The tools available in flies allow precise manipulation of genes and the signaling properties of cells in the brain and periphery. We suspect that the high level of molecular conservation between flies and humans will extend to the roles of molecules in behavior.
Current research focuses on the actions of the widely abused drug alcohol, and the motivational properties of internal state imbalances. The long term goal is to understand how motivational states are represented in the brain.
Research Projects
Mechanisms of Alcohol Action and Addiction
Alcohol is the most widely used and abused drug in the world. Understanding the neural and genetic mechanisms of alcohol action is critically important for designing effective treatments for alcohol abuse. Further, alcohol taps into some of the most primitive circuitry of the brain, giving us a means to study how these circuits work. Flies and humans share an evolutionarily ancient interest in ethanol, and flies exhibit many behaviors that model features of addiction in higher organisms. For example, ethanol exposure causes lasting adaptations (sensitization and tolerance) to both its pleasurable and aversive effects. These simple forms of behavioral plasticity can facilitate increased ethanol intake, which is an important predictor for the development of alcohol use disorders. Flies can also develop a preference for ethanol, and they find it rewarding.
Genetic programs dictating ethanol tolerance
Gene expression changes reveal molecular clues as to how the brain is changed by a single exposure to ethanol. We screened for ethanol response genes and subsequently tested flies mutant for particularly interesting genes for their ability to develop ethanol tolerance. We are now focused on ethanol response genes that can can themselves regulate gene transcription, as this class of molecules has the potential to drive lasting alterations to brain function.
Thirst Representation in the Brain
Thirst is a fundamental motivational drive that is critical for survival of animals. It drives a stereotyped series of behaviors to seek and then ingest water to repletion. Moreover, thirst competes with other motivational drives, especially hunger, to choose behaviors to meet the greatest current need. Determining how thirst is represented in brain circuitry and neurochemically will help us understand the basic mechanisms of the coding of motivation in the brain, the means by which complex behavioral sequences are organized, and how maladaptive motivational states in addiction and psychiatric disorders occur.
Stress Resilience
External stressors induce neurally encoded and cellular stress response pathways. Protein ubiquitination is a highly regulated posttranslational mechanism for changing protein stability and function that controls many stress pathways. We are interested in how removal of ubiquitin by deubiquitinases contributes to stress regulation, by focusing on the function of a particular deubiquitinase that is conserved from yeast to humans. Our goal is to uncover a novel biochemical pathway and its physiological function in the whole organism.
Techniques
The fruit fly is a classic model organism for genetic studies. Over one hundred years of research with flies has resulted in an unparalleled set of genetic tools for manipulating gene and cellular function. We use these tools to precisely control gene expression and to manipulate the transmission properties of neurons and glia in the adult brain. We also use molecular, biochemical and immunohistochemical techniques.
Part of the fun of studying animal behavior is the opportunity to develop new devices and quantitative behavioral assays. An example is the automated locomotor tracking device that we built to assay the effects of acute ethanol vapor on fly locomotor activity.
Flies in the eight chambered booz-o-mat chamber are filmed directly onto a computer. The flies are detected automatically on the films (below left) and the paths of multiple individuals are traced (below right).
The position and other information about individual flies at any given time is determined computationally, and we developed algorithms to extract specific parameters such as locomotor speed. This basic assay was central to our discovery of a dopaminergic neural circuit in the central brain that increases walking speed and mediates the locomotor stimulant properties of ethanol. The locomotor tracking device adapts easily to new assays, including those that we developed for studying feeding behaviors.
