Precise modulation of neurotransmitter levels is essential for apt functioning of the nervous system. Dopamine is an important brain neurotransmitter that plays a critical role in movement control across species, ranging from microscopic invertebrates to larger mammals, including humans. The levels of dopamine are regulated tightly and precisely through modulation of dopamine release into the space between connected neurons as well as clearance of dopamine from that space. The physiological mechanisms underlying the modulation of synaptic dopamine remain unclear. Towards the goal of elucidating the mechanism of dopamine modulation, the simple yet powerful C. elegans model with a well-defined 302-neuron nervous system is used in this project to uncover the in vivo function of dopamine auto-receptors, presynaptic receptors on dopamine-releasing neurons. With only 8 dopaminergic neurons, the C. elegans model allows dissection of dopaminergic signaling at a level not feasible in other, more complex organisms. Given the similarities of the mammalian and C. elegans dopaminergic systems at the cellular and molecular levels, results from this work will inform understanding of the interactions between dopamine modulators in the mammalian nervous system and thereby inform movement control more generally. This research also provides valuable educational training in science and technology for high school, undergraduate, and graduate students at Delaware State University (DSU), a predominantly undergraduate institution that is a Historically-Black College and University (HBCU). In addition to providing advanced training to an under-represented population of students, this endeavor helps strengthening the research environment at DSU.
Mechanisms of synaptic vesicular fusion and neurotransmitter clearance are highly controlled processes whose finely-tuned regulation is critical for functioning of the nervous system. Auto-receptors have been suggested to regulate neuronal function by affecting neurotransmitter synthesis, vesicular release and neurotransmitter clearance. While auto-receptors for various neurotransmitters have been known for decades, the mechanisms by which they act remain unclear. The overarching goal of this project is to understand how neuronal function and behavior are regulated through real-time precision in synaptic neurotransmitter levels in vivo. The significance of dopamine is underscored by the fact that it critically influences a wide range of behaviors with conserved cellular roles across phylogeny. This research exploits the simple yet well-defined nervous system of Caenorhabditis elegans with its powerful genetics of the model, combined with its transparent body that allows imaging of individual dopaminergic synaptic boutons in living animals. The hypothesis to be tested here is: dopamine auto-receptors modulate neuronal activity through a negative feedback loop controlling synaptic vesicle fusion, and they fine-tune their function via cross-talk with other dopamine regulators such as the membrane dopamine transporter . The experiments will test the behavioral and physiological function of dopamine auto-receptors in vivo while visualizing individual synapses in live animals with fluorescent resonance after photo-bleaching, an approach not currently feasible in mammals. These studies will advance the field in terms of establishing the modulatory effect of D2 auto-receptors on synaptic dopamine, and test its functional interactions with other dopamine modulators.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
