My laboratory uses the fruit fly (Drosophila melanogaster) and rats as genetic model organisms to study the molecular and cellular basis of diverse biological processes and diseases, including hunger- and reward-driven impulsive eating, appetitive odor perception and motivation, sensory integration, pain and stress resiliency, social behavior, control of body weight gain,eating disorders, and alcohol abuse. Neurobiological researches conducted through animal models such as the fruit fly are of great significance due to the high degree of gene homology between humans and these animals as well as their parallel brain functions regulated by well-conserved molecular and neural systems.
Central regulation of appetitive and consummatory responses to palatable food
Drosophila larvae have a highly evolved yet numerically simpler nervous system, providing a powerful model for investigating sensory, cognitive and motor functions related to diverse aspects of feeding response. We have identified a diverse array of conserved neural substrates and mechanisms that regulate energy-state and sensory cue-driven hyperphagic responses to palatable food. For example, appetite for palatable food can be enhanced in humans and other animals by additional sensory cues such as food odor when coupled with taste. A dopamine pathway has now been identified that mediates appetitive odor-aroused overeating of sugar-rich food. We have also found that a novel neural activity of the VEGFR system that promotes hunger-driven overeating of palatable food in both flies and rats. In addition, the VEGFR system plays a novel role in a separate neural mechanism that controls body weight gain in both animals.
Higher-order olfactory representations and processing in the brain
Olfaction is considered to be an evolutionarily primitive sense. The combinatorial sensory representations of volatile compounds related to food are enormously complex. At present, how such diverse and behaviorally meaningless olfactory inputs are received and integrated in the brain to acquire motivational significance and drive reward-seeking behaviors remains poorly understood in any organism. We have developed a genetically tractable Drosophila larva model for investigating molecular and cellular mechanisms underlying higher-order olfactory representations and processing. Our recent study provides the first demonstration of the role of a DA neuron-mediated neural circuit in appetitive odor perception and motivation by contributing to a population coding mechanism.
Neural signaling mechanisms pertaining to risk-prone foraging and work motivation
We use 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. So far, an array 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, procure and consume undesirable or less-preferred foods. These and other studies now demonstrate that NPF is a master regulator of diverse motivation systems such as incentives for the larva to work for food and engage in risky foraging behaviors.
Roles of Neuropeptide Y in anti-nociception and stress-induced social behavior
Human neuropeptide Y (NPY) plays a prominent role in management of stress response and emotion. NPF, the fly counterpart of NPY, also displays parallel activities, including promotion of resilience to diverse stressors, suppression of chronic pain-like state and control of stress-induced social behavior. We have shown that the NPF receptor, NPFR1, attenuates Ca(2+) influx mediated by fly TRPA and rat TRPV1 channels. These findings suggest that suppression of TRP channel-mediated neural excitation by the conserved NPF/NPFR1 system is a major mechanism for attaining its broad anti-stress function.
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 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. These studies should contribute to the better understanding of genetic predispositions of alcohol use disorders and the development potential therapeutics for alcohol abuse and addiction.
Branch A, Bobilev A, Negrao NW, Cai H, Shen P. (2014) Prevention of palatable diet-induced hyperphagia in rats by central injection of a VEGFR kinase inhibitor. Behav Brain Res. 278C:506-513.
Ting Z, Branch, A, Shen P. (2013) An Octopamine-mediated Circuit Mechanism Underlying Controlled Appetite for Palatable Food in Drosophila Proc Natl Acad Sci U S A.110:15431-6.
Wang Y, Pu Y, Shen P. (2013) Neuropeptide-gated perception of appetitive olfactory inputs in Drosophila larvae. Cell Rep. 3:820-30
Chen, J. Zhang, Y. and Shen, P. (2010) Protein Kinase C Deficiency-induced Alcohol Insensitivity and Underlying Cellular Targets in Drosophila Neuroscience 166: 34–39.
Xu, J. , Li, M. and Shen, P. (2010) A G-protein Coupled Neuropeptide Y-like Receptor Suppresses Behavioral and Sensory Response to Multiple Stressful Stimuli in Drosophila. J. Neuroscience 30:2504 –2512.
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, 11: 676-82.
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, 156: 42-47.
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.
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
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.
Wu, Q., Wen, T., Lee, G., Park, J. H., Cai, H. and Shen, P. (2003) Developmental
Control of Foraging and Social Behavior by the Drosophila Neuropeptide Y-like System. Neuron, 39: 147-161
Gaczinski, S.F. Brown, M. R. Shen, P., and Murray T. F., and Crim, J.W (2002) Characterization of a functional neuropeptide F receptor from Drosophila melanogaster. Peptides. 23:773-80.
Brown, M.R, Crim, J.W., Arata, R.C., Cai, H.N, Chun, C, and Shen, P. (1999) Identification of a Drosophila brain/gut peptide related to the neuropeptide Y family Peptides, 20:1035-42.