Neuromodulator and neurotransmitter signaling pathways are critical for brain function and are targeted for the treatment of diverse neurological and psychiatric disorders. The nervous system of the simple invertebrate Caenorhabditis elegans is endowed with many of the same neurotransmitters and neuromodulators that are critical for brain function and whose dysfunction is linked to human disease. We study a C. elegans neural circuit in which sensory neurons use neuropeptides to modulate serotonin neurons that drive reproductive behavior and the neurotransmitter glutamate to mediate avoidance behavior. Genetic analysis of the function of this circuit and its development permits the discovery of molecular mechanisms required in vivo for inhibitory neuropeptide signaling and excitatory glutamate signaling. Sensory neurons that coordinately regulate locomotory and reproductive behaviors are activated by carbon dioxide (CO2) evolved by microbial respiration. This simple circuit, therefore, also offers the opportunity to study mechanisms by which neurons sense respiratory gases - a critical chemosensory modality that in humans controls breathing rhythms and remains poorly understood at the molecular level. Our studies of this circuit have yielded genes that are conserved between invertebrates and humans, and we have discovered functions for these genes in transcriptional control of gene expression during sensory neuron development, CO2-chemosensing, control of glutamate release from neurons, and control of neuronal excitability by neuropeptide receptors. Our studies have yielded more genes that function in these processes and that remain to be characterized, and we expect that this sensory-motor circuit will continue to serve as a powerful platform for the discovery of genes that function in neuromodulator and neurotransmitter signaling and that might be eventually be developed as therapeutic targets.

Public Health Relevance

Neuromodulator signaling pathways are important therapeutic targets for the treatment of brain disorders such as schizophrenia, autism, addiction and Parkinson's disease. We have established a powerful experimental system that uses the invertebrate C. elegans for the discovery of genetic mechanisms that function in neuromodulator signaling and in the development of neural circuits that use neuromodulators to control behavior. The mechanisms we have discovered employ genes conserved between invertebrates and humans, and they offer new opportunities to understand and target neuromodulator signaling for the treatment of psychiatric and neurological diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Unknown (R35)
Project #
5R35GM122573-02
Application #
9552216
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Sesma, Michael A
Project Start
2017-09-01
Project End
2022-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10010