Drosophila melanogaster as a translational model to study serotonin
The fruit fly is a very powerful and sophistocated model genetic organism. The fly brain contains over 100,000 neurons in defined circuits and neuropil that utilize essentially the same neurotransmitters as higher organisms. As such, the fly demonstrates concerved behaviors with mammals and humans including activity, sleep, learning and memory, navigation, courtship, and responses to drugs.
The fly expresses four serotonin receptors similar in structure and function to mammalian serotonin receptor (5-HT1A, 5-HT1B, 5-HT2A, 5-HT7), and one serotoin receptor that is structurally divergant (5-HT2B). Each is couples to similar signal transduction pathways as their mammalian couterpart and they respond to many of the same drugs. We have developed genetic tools to map and study the function of several of the fly serotonin receptors in the CNS and have identified key roles in behaviors for them.
We have found that: Learning and memory involves all receptor subtypes, with differential roles for each in acquisition, consolidation, and recall. The 5-HT7 receptor is involved in courtship such that loss of activity in either males or females elicits a loss of interest in mating. 5-HT1A/B receptor activation increases aggression in males, whereas 5-HT2 receptor activation reduces aggression between males. 5-HT2 receptors are involved in visual acuity and circadian behaviors, among others. We are continuing our study of the role of serotonin and its receptors in fly behaviors relavant to psychiatric disorders like drug abuse and depression.
We have translated DREADD receptor technology to flies, and have demonstrated it to be a powerful method for modulation of neuronal activity and receptor signaling processes. We are currently using DREADDs to elucidate the curcuitry underlying the sexually dimorphic responses to CNS stimulants and the role of serotonin in these processes.