A non-mammalian model for neurofunctional studies of vertebrate dopamine signalling

Neurons of the mesodopamine system regulate voluntary motor behaviour and reward prediction, and are severely disrupted in disorders such as Schizophrenia and Parkinson's disease. Mammalian electrophysiological studies have been central to delineating physiological and pathophysiological functions of the mesodopamine system. However, these have significant ethical shortcomings. In particular, electrophysiology methods are invasive and have the potential to cause pain, suffering and lasting distress. Technical limitations also have an impact on the number of mammals used for study: a complete understanding of neuronal function requires knowledge of (I) cellular and (II) sensory mechanisms controlling dopamine neuron firing. Ideally, a single experimental procedure could be used to study both phenomena. Unfortunately, this ideal cannot be met with mammalian models, so two independent procedures must be used. This shortcoming further increases the number of protected rodent and primate species used in mesodopamine studies.

We propose to develop a larval zebrafish preparation that can be used as an ethically superior alternative to mammalian mesodopamine models. We will establish protocols for conducting patch clamp recordings from dopamine neurons that innervate the zebrafish subpallium, a structure that corresponds to the mammalian striatum. Recordings will be obtained from awake larvae so data on the cellular and sensory control of dopamine neuron activity can be collected simultaneously, thereby reducing use of animals. These methods will be used to characterise dopamine pathways controlling reward seeking behaviour and motor execution. As experiments will be conducted on larvae that are not protected under the Animals (Scientific Procedures) Act 1986, ethical concerns will be minimised. Data derived from this project will improve understanding of zebrafish dopamine circuits and will be used as a framework for developing ethically superior models of dopamine diseases.