Fighting Obesity: The Drosophila-Inspired Search for the Mediating Neural Circuitry of Appetite

2 David Lee

Table of Contents Fly Studies ........................................................................................................ 4 Case Studies...................................................................................................... 4

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Outline

I. Introduction II. Research Methods A. Qualitative B. Quantitative C. Aesthetic III. Conclusion

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David Lee Mr. Heil Computer Applications 10 August 2011 Fighting Obesity: The Drosophila-Inspired Search for the Mediating Neural Circuitry of Appetite Fly Studies
Deep within a human dwelling, a solitary fly makes its first attack on an unattended pizza slice. The enticing aromas coming from the cheese and the greasy toppings encourage the fly as it feasts. However, a little ways into the feast, a switch is flipped somewhere in the flys body. All of a sudden, the pizza, so alluring to the fly before, now instead repulses it. Driven by this impulse, the fly brushes the last bits of the cheese from its forelegs and takes off into flight. What made the fly reject its food and fly away? This satietybased switch in one of our ubiquitous insects may hold the key to one of Americas greatest health problems: obesity. Although obesity has a variety of causes, such as culture, psychological problems, age, physical inactivity, and medical problems (St.Vincent Health, 2006), it can also be affected by the genetic makeup of the individual, such as the lack of genes to turn off ones desire to eat even after the hunger is satiated. Such genes have already been identified in mice, the ob and the db, in which the absence of the genes makes the mice grow to gargantuan proportions (Campbell and Reece, 8th Edition). Targeting the neural pathway of the corresponding genes that mediate such gluttonous behavior would lead us to at least a partial cure of obesity. Case Studies
student 8/10/11 12:45 PM Comment: Animal cruelty!! student 8/10/11 12:47 PM Deleted: u student 8/10/11 12:45 PM Deleted: most student 8/10/11 12:44 PM Comment: I agree! student 8/10/11 12:46 PM Deleted: dsfj

5 David Lee Drosophila melanogaster, the fruit fly, is an ideal organism for identifying the neural circuitry because of its simplistic brain and many genetic tools available to it (NYU Suh Labs, 2009). Furthermore, as shown in previous studies, many behavioral genes and their signaling pathways are preserved from flies to humans, which means that the flies neural circuitry would be a relevant model to study that of people. In identifying the correct neural circuit, one must bear in mind that each gene codes for a functional unit in a signaling pathway while the brain is composed of individual neural circuits (NYU Suh Labs, 2009). Therefore, similar behaviors can use the same signaling pathway while they are processed in distinct neural circuits (NYU Suh Labs, 2009). An example of this would be two different types of memory (such as fear and spatial) that are processed in the same pathway but different circuits; they are controlled by both the cAMP second messenger signaling and similar cellular mechanisms but fear memory is processed by the amygdala, while the spatial memory is processed by the hippocampus (NYU Suh Labs, 2009). Consequently, the identification of the signaling pathway controlled by a single gene wouldnt be the answer, for the correct neural circuit (and the correct group of neurons to be treated) is still yet to be identified. However, current research is succeeding, both in tracing the specific neural pathway and in identifying chemicals connected to satiation. A hypothesis put forward by my lab Principal Investigator, Dr. Suh, is that the flies emit dSO, drosophila Stress Odorant, when under electrical shock or mechanical stress (NYU Suh Labs, 2009). When our lab performed a Gas Chromatography and Mass Spectrometry (GCMS) analysis on dSO, we were able to isolate carbon dioxide as one of its principal compounds. Afterwards, we used calcium imaging to identify sensory neurons activated by CO2, and we found Gr21a receptors on the neurons which signal the avoidance of

6 David Lee CO2 to the fly (NYU Suh Labs, 2009). The receptors indicated that the neurons were specific to this task, encouraging our beliefs that we can map the neural circuit to a particular behavior using the techniques at hand, such as calcium imaging and electrophysiological techniques (NYU Suh Labs, 2009). Furthermore, when we ran TMaze assays (T-Mazes are composed of elevators the glass tube where the flies are stored , and two opposing tubes containing different compounds. When the elevator is lowered, the flies get around sixty seconds to make a choice), the starved flies and sated flies alike had similar responses to different chemical odors. However, to the appetitive odor, the starved flies were greatly attracted while the sated flies were repelled. This supported our labs theory that the appetitive odor, although composed of many different odors, were singular to the fly, and a group of neurons would most likely recognize this odor in the flys neural circuitry. Although humans are different from drosophila by approximately 2.9 billion base pairs (US Dept of Energy Office of Science, 2008), the same neural circuitry for innate behaviors persists. Thanks to this convenience, the neural circuit in the drosophila that we will discover using modern molecular technologies will also be applicable to ourselves. If an obese persons circuitry is found to be defective, we could induce the neurons to express receptors for the avoidance of the appetitive odor. Potentially, this could be a very powerful treatment. Currently, most of the obesity treatments are not very effective and often have severe side effects (such as valvular heart disease, which was reported to occur in association with the use of certain appetite-suppressant medications) (NIDDK Weight Control Information Network, 2002). Obesity is also a burgeoning problem: seventy-two million adults, roughly 30% of the population, are obese, and this number is ever growing (Center for Disease Control and Prevention, 2005~2006). Thus, such a treatment would impact millions of people,

7 David Lee helping them to live healthier and longer lives by eliminating obesity-related complications, which range from heart failure to mental degeneration. Ironically, this may mean that an indiscriminate food scavenger such as the fly holds the cure to a much trimmer and healthier America. You can find this spreadsheet by clicking on the spreadsheet icon on the class homepage under the red bonus star icon. When you post your homework link to the google doc spreadsheet, do not edit or delete any other student's information or their rows, only your own. I have access to a complete history of all the edits to the spreadsheet and who did it. There will be major consequences for those who purposely delete, edit, or write in blanks that are not their own. And you are not allowed to post a posterous article with nothing in it and post to the spreadsheet as

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