Functional mapping of the extrasynaptic dopaminergic neurotransmission and dopaminergic circuits of C. elegans

Dopamine is a neuromodulator involved in many key functions of the nervous system, including learning, motivation, reward, and movement. Furthermore, disruption of dopaminergic systems is central to numerous disorders/diseases, including addiction, depression, Parkinson’s Disease and Schizophrenia. While dopamine receptor (DAR) agonists have proven to be valuable therapeutic agents for alleviating disease symptoms, their broad expression across the nervous system results in significant off-target side effects. Thus, there is a strong therapeutic need for tools that allow manipulation of dopaminergic circuits with high temporal and spatial precision. Furthermore, although the differential expression of DAR subtypes (e.g., D1- and D2-like receptors) contributes to specificity in endogenous dopaminergic modulation of neural circuits, a precise understanding of how dopamine acts extrasynaptically to influence such a broad range of circuits and behaviours remains lacking. In this project we set out to 1) develop and validate photoswitchable compounds that can selectively activate specific DAR subtypes, 2) test these compounds in Caenorhabditis elegans, allowing both in-vivo validation of the compounds and research on the mechanisms by which extrasynaptic dopamine modulates neural circuits. C. elegans is an ideal model for this purpose, given its high genetic amenability, optical accessibility, and well-characterised nervous system and behavioural repertoire. Currently we have validated photoswitchable dopamine receptor agonists in C. elegans using behavioural tests and generated C. elegans strains that will allow simultaneous recording of neuronal activation and identification of D1-receptor positive neurons.