PING SHEN
Associate Professor
Ph.D., 1988
Washington University School of Medicine
RESEARCH
My laboratory uses the fruit fly, Drosophila melanogaster, as a genetic model organism to study the molecular and cellular basis of diverse biological processes and diseases, which include self-motivation, pain and stress resiliency, social behavior, eating disorders and alcohol abuse. Neurobiological researches conducted through fly models are of great significance due to the high degree of gene homology between fruit flies and humans and their parallel brain functions regulated by well-conserved molecular and neural systems.
Signaling Mechanisms Pertaining to Self-motivation and Risk Taking
All animals have evolved highly optimized strategies to modulate reward and risk responses with respect to favorable and adverse circumstances. Under life-threatening conditions such as prolonged food deprivation, animals tend to become more risk-prone and display increased willingness to perform stressful tasks. We have pioneered the use of the fruit fly model to study how conserved molecular signaling pathways in defined neuronal circuits regulate motivated and risk-prone behaviors in response to external and internal stimuli. We conduct genetic screening to uncover evolutionary conserved genes that regulate motivated reward-seeking and risk-taking behaviors. The molecular and biological functions of such genes are subsequently analyzed using a combination of molecular, imaging and behavioral approaches. So far, a list of conserved genes and associated signaling systems have been identified and characterized.
For example, unless severely starved, fly larvae prefer to avoid foods that are hard, bitter or cold. We have shown that a gene encoding a brain peptide (neuropeptide F or NPF, the sole fly member of the neuropeptide Y family found widely among organisms from humans to worms) is critical in the self-preservative motivation of starved animals to seek and consume undesirable or less-preferred foods. We have made two important observations. First, NPF signaling-deficient larvae display normal feeding responses as wild type animals to rich, palatable foods. Second, increased NPF signaling by over-expressing its G-protein coupled receptor NPFR1 in well-fed larvae is sufficient to trigger risk-taking and motivated food procurement without affecting their feeding response to rich, palatable foods. These findings suggest that npf is specialized to provide the incentive for the larva to work for food and engage in risky foraging behaviors. We are currently expanding our efforts into the investigation of other regulatory genes with known or unknown molecular functions, with a long-term goal of unraveling the complete signaling pathway for risky and motivated behaviors using this larva model.
The Signaling Network for Hunger-driven Behaviors
Stressful events, such as food deprivation, can drastically alter an animal’s physiological state and behavior. In fasting larvae, an insulin-like signaling pathway senses the metabolic state and organizes the onset of diverse hunger-driven behaviors, including NPF-mediated motivated foraging activities, and NPF-independent intake of palatable food. An increase of insulin-like signaling in fasting animals was shown to be sufficient to attenuate all hunger-driven behaviors. We are currently investigating how fly insulin-like receptors negatively regulate the activities of diverse neurons that control distinct hunger-driven behaviors. These studies may provide novel insights into mechanisms underlying human eating disorders.
Developmental Regulation of Stressor-induced Social Behavior
Diverse animals display social responses (e.g., grouping) to stressful stimuli. Drosophila larvae display grouping behavior in order to cooperatively cope with stressful conditions such as hunger, harmful microbes and aversive chemicals. Older postfeeding (or wandering) larvae aggregate on fruit juice-containing hard media and display a cooperative burrowing behavior (which likely helps the larvae to quickly reach pupation sites below top soil). Two signaling modules regulate social burrowing: 1) a sensory module involving TRPA channels and protein kinases that detects fruit juice or sugar and relays the signal to the central nervous system; 2) a timing module involving NPF and its G-protein coupled receptor NPFR1, which developmentally program the onset of food-averse behaviors by suppressing the sensory module in younger feeding larvae. We have recently obtained evidence that this NPF/NPFR1-mediated control module represents a conserved anti-nociceptive mechanism capable of suppressing ion channels (e.g., fly TRPA and mammalian TRPV1) for sensing pain, hot chili peppers, and wasabi. We are currently investigating the molecular mechanisms underlying the anti-nociceptive activity of the NPF/NPFR1 pathway.
Molecular Genetic Analysis of Alcohol-related Behaviors in Drosophila
Sensitivity to alcohol intoxication varies greatly among individuals. Alcohol insensitivity in adolescents is a strong predictor of human alcoholism. We have uncovered a number of conserved signaling systems that modulate alcohol sensitivity in flies and mammals. For example, higher activities of neuropeptide Y (NPY) in mammals and its counterpart NPF in flies render the animals more susceptible to alcohol sedation, while attenuated NPY/NPF signaling leads to opposite phenotypes. Another important finding is the dual regulatory roles of many of these conserved signaling molecules in both alcohol and stress response. We are currently investigating how NPF and other conserved neural signaling pathways modulate the behavioral effects of alcohol. These studies may help prevent the development of alcohol use disorders and identify potential therapeutic targets for alcohol abuse and addiction.
SUPPORT STAFF
Jiang Chen Post Doc Mo Li Post Doc Jie Xu Grad Student Yan Zang Research Technician III REPRESENTATIVE PUBLICATIONS
CONTACT INFORMATION office (706) 542-1220, lab (706) 583-0593, fax (706) 542-4271, pshen@cellmate.cb.uga.edu
SEE ALSO Biomedical & Health Sciences Institute
NAMEPOSITION
E-MAIL
Xu, J., Sornborger, A. T., Lee, J.K. and Shen, P. (2008) Drosophila TRPA channel modulates sugar-stimulated neural excitation, avoidance and social response. Nature Neuroscience, Epub 2008 May 11.
Chen, J., Zhang, Y. and Shen. P. (2008) A Protein Kinase C Activity Localized to Neuropeptide Y-like Neurons Mediates Ethanol Intoxication in Drosophila melanogaster. Neuroscience, Epub 2008 July 10.
Lingo P.R.†, Zhao, Z.† and Shen, P. (2007) Co-regulation of cold-resistant food acquisition by insulin- and neuropeptide Y-like systems in Drosophila melanogaster. Neuroscience, 148: 371-374. † authors contributed equally to the work.
Wu Q., Zhao, Z and Shen, P. (2005) Regulation of aversion to noxious food by Drosophila neuropeptide Y- and insulin-like systems. Nature Neuroscience, 8: 1350-5
Wu Q., Zhang Y, Xu, Jie and Shen, P. (2005) Regulation of hunger-driven behaviors by neural ribosomal S6 kinase in Drosophila Proc Natl Acad Sci U S A. 102:13289-94.
Wen, T, Parrish C.A., Xu D., Wu, Q., and Shen, P. (2005) Drosophila neuropeptide F and its receptor, NPFR1, define a signaling pathway that acutely modulates alcohol sensitivity. Proc Natl Acad Sci U S A. 2005 102:2141-6.