Neuropeptides are signaling molecules secreted by neurons and other cell types to regulate a variety of critical physiological processes and behaviors, including circadian rhythms, metabolism, sleep, feeding, sexual activity, etc. Defects in these processes cause serious pathological conditions, including narcolepsy, insomnia, diabetes, obesity, and depression. Understanding the causes and improving treatment methods of the many diseases attributable to neuropeptidergic dysfunction requires more complete knowledge of how these signaling modules function in vivo. The long-term goal is to understand how neuropeptides function within neuronal circuits to regulate animal behavior. We investigated the functional role of a conserved neuropeptide Pigment Dispersing Factor (PDF) in the genetically tractable model organism Caenorhabditis elegans. While PDF and its homolog Vasoactive Intestinal Peptide (VIP) mediate the circadian clock in insects and mammals, respectively, PDF function in worms is unclear. Two PDF encoding genes, pdf-1 and pdf-2, were recently identified in C. elegans. Interestingly, PDF-2 expression partially overlaps with LITE-1, a putative GPCR identified as a light sensor in worms, suggesting that worm PDF could play a role in a non-circadian but light-modulated behavior. In preliminary studies, we have found that PDF is involved in light-response behavior of worms. Null mutant worms lacking PDF-2 show defects in light avoidance behaviors similar to those of worms lacking LITE-1. We will employ a variety of genetic manipulations in conjunction with robust behavioral assays to determine if PDF-2 mediates worm locomotor response to light. We will achieve those goals through the following specific aims: (1) Test hypothesis that PDF-2 is a key modulator of photophobic behavior (2) Dissect cellular basis for PDF-2 mediated UV avoidance (3) Characterize physiological effect of PDF-2 in UV avoidance circuit The first aim will build upon preliminary observations and determine the role of the pdf-2 gene in behavioral responses to light.
The second aim will identify the PDF-2 secreting cells and the PDF Receptor (PDFR)- expressing cells involved in light avoidance behavior.
The third aim will use a genetically encoded calcium sensor to determine the physiological consequences of PDF-2 on PDFR-expressing cells in light avoidance. This research will explore the conserved roles for PDF in light-sensing circuits and provide mechanistic understanding of neuropeptide signaling in neuronal circuits in vivo. Given the sequence and functional construction of PDF-like peptides, these studies are likely to reveal how PDF signaling regulates behaviors in mammals and yield insight into how defects in neuropeptide signaling can lead to neurological disorders.

Public Health Relevance

Neuropeptides regulate a variety of critical physiological processes and behaviors, including circadian rhythms, metabolism, sleep, feeding, sexual activity, etc. Deficiencies in neuropeptide function have been directly linked to a diversity of diseases, such as narcolepsy, obesity, and depression. Detailed molecular and cellular characterization of these molecules would greatly advance our understanding of basic physiology and neurobiology, and thereby facilitate treatment of human disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS080628-01A1
Application #
8527097
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
He, Janet
Project Start
2013-03-01
Project End
2015-08-31
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$42,232
Indirect Cost
Name
Yale University
Department
Physiology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520