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 motivatonal properties of food. The long term goal is to understand how cues with positive value (food, drugs) are represented in the brain.
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.
Glial regulation of ethanol tolerance
The active participation of glia in nervous system function has become evident in recent years, and both physiological and pathological responses of glia to ethanol have been documented. The fly brain harbors five distinct classes of glia that appear to carry out specific classical glial activities including neuronal trophic and structural support, electrical insulation, and partitioning of the brain and the circulatory system. How ethanol impacts glial-neuronal communication, and the role of glia in the complex alterations in brain function that accompany the development of ethanol tolerance, are important issues that we can begin to address in flies.
Satiation state is a fundamentally important driver of animal behavior: food deprivation can strongly motivate food seeking. Dysregulation between metabolic need and food intake is common in humans and can cause great hardship and even death. Eating disorders, such as anorexia nervosa, and substance use disorders share comorbidity for psychological disorders of mood and anxiety, and they often co-occur in individuals. Mammalian brain regions that are co-opted by drugs of abuse also regulate eating behaviors, using overlapping molecular pathways. What is the extent of this functional overlap? Are shared circuit elements used similarly in eating behaviors and by drugs of abuse? How do eating disorders differ from addiction? We developed new quantitative behavioral assays and carried out a forward genetic screen to find genes that regulate the motivation to find food and to eat it. We are interested in finding out how the affected genes and the neural circuits in which they presumably function regulate responses to both food and to ethanol.
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.