A fundamental requirement of normal brain function is to filter relevant from irrelevant sensory information using criteria that change depending on the immediate behavioral context. One example is a sensorimotor gating phenomenon known as prepulse inhibition (PPI), in which the startle reflex that would normally be evoked by an intense stimulus is inhibited by a weaker preceding cue. Deficits in PPI are a common feature of neurological disorders that entail more general problems with sensory filtering, including schizophrenia, Tourette?s, and obsessive-compulsive disorder. The neuronal mechanisms of PPI are incompletely characterized, though it is known to be critically dependent on dopamine, and a common treatment for all of the disorders mentioned above is the administration of drugs that target dopaminergic systems. Developing a more complete understanding of the basic biological mechanisms that drive PPI, and particularly those that involve dopamine, will generate hypotheses for the neural bases of these and other diseases. This project will exploit the experimental leverage offered by the larval zebrafish to investigate the means by which a genetically-defined population of dopamine neurons located throughout the diencephalon mediates audiomotor PPI. By combining behavioral recordings with calcium imaging, optogenetics, whole-brain activity mapping, and neuroanatomy, the project will achieve three goals: (1) Identify the specific dopaminergic nuclei within the population that participate in audiomotor processing; (2) Test the hypothesis that rapid modulation of activity within these neurons is essential for behavioral inhibition; (3) Assess the anatomical and likely functional targets of dopamine release from these cells in the context of PPI. The results of this work will be a detailed model for how distributed activity within a specific population of dopaminergic neurons shapes sensorimotor gating, and a better understanding of how similar networks might be affected in human disease.
Schizophrenia, Tourette?s syndrome, obsessive-compulsive disorder, and several other neurological disorders are characterized by the brain?s inability to filter relevant from irrelevant sensory information and to respond accordingly. This project will characterize the neural mechanisms that underlie one particular form of sensory filtering, called prepulse inhibition, which is affected by such pathologies. The results will provide a better understanding of the biological bases of such disorders.
