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This study explores the role of basal forebrain DA/5HT neurons in reward-associated behavior in zebrafish. It investigates the development of these neurons and their regulation using genetic analysis and mutant models.
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Development of DA and 5HT neurons involved in reward-associated behavior in zebrafish Su Guo, Ph.D. University of california, San Francisco
Basal forebrain DA and 5HT neurons 3-day old zebrafish labeled with anti-TH and 5HT antibodies
Questions • Do zebrafish have reward-associated behavior? • Experience-dependent morphine preference • Do the basal forebrain DA/5HT neurons play a role in this behavior? • The too few mutant • How is the development of basal forebrain DA/5HT neurons regulated? • The foggy mutant
Zebrafish: a vertebrate genetic model organism Small-size High fecundity Rapid development In vivo tracing of biological processes Easy to maintain In large numbers Optically transparent
What is reward-associated behavior? • A prior exposure to a substance elicits a preference behavior for the substance: • Spend more time in the substance-paired side (CPP) • Self-administer the substance
Studying reward-associated behavior in larval zebrafish • Larval zebrafish are amenable to genetic analysis and the study of cellular mechanisms • Larval zebrafish are free-living (food hunting, escaping) • The nervous system of larval zebrafish is more plastic than adult zebrafish.
drug water Pre-expose larval Zebrafish to the drug draining Test their preference for the drug in the choice chamber Choice chamber
Larval zebrafish show experience-dependent preference for morphine
The basal forebrain DA/5HT neurons are required for morphine preference behavior
tfu Zebrafish: adapted from Rink and Wullimann, 2002 Mammals: adapted from Kandel’s Principles of Neural Science Functional analogy of zf basal FB to mammalian MB DA neurons
How is the development of basal FB DA and 5HT neurons regulated? • Will the mechanisms be homologous to mammalian FB or MB neurons? • What are the genes and pathways involved in the development of these neurons?
Mutations affecting the development of basal FB DA/5HT neurons • too few • motionless • twin-of-motionless • foggy
The foggy mutant WT foggy
The importance of regulating transcription elongation during development promoter Transcription initiation Transcription elongation
Activator Repressor The foggy mutation selectively disrupts its repressor activity
Question • What genes are de-repressed that leads to defects in DA/5HT neuron development? • Micro-array study • How is foggy’s repressor activity regulated during development? • Focus on the function of the C-terminal domain, where the foggy mutation resides.
Summary • Zebrafish is an attractive genetic model organism to study: • the development of specific neuronal types. • The developmental alteration that leads to abnormal reward-associated behavior.
Acknowledgements Reward-associated behavior in larval zebrafish Sandrine Bretaud Brent Lockwood Foggy downstream tergets Keerthi Krishnan Foggy regulation Jae-yeon Jeong Arnon Rosenthal (Rinat Neuroscience) Mark Fishman (Novartis) Wolfgang Driever (University of Freiburg)