Date of Graduation

12-2016

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Michael J. Galko, Ph.D.

Committee Member

Edgar T. Walters, Ph.D.

Committee Member

Howard Gutstein, M.D.

Committee Member

Herman Dierick, Ph.D.

Committee Member

Kartik Venkatachalam, Ph.D.

Abstract

Organisms from flies to mammals utilize thermoreceptors to detect and respond to noxious thermal stimuli. Although much is understood about noxious heat avoidance, our understanding of the basic biology of noxious cold perception is gravely minimal. Numerous clinical conditions disrupt the sensory machinery, such as in patients suffering from tissue damage (from wound or sunburn), or injury to the peripheral nerves, as in patients with diabetes or undergoing chemotherapy. Our goal is to determine the genetic basis for noxious cold perception and injury-induced nociceptive sensitization using the genetically tractable Drosophila model. Using a novel "cold probe" tool and assay we found larvae produce a mutually exclusive set of reactive behaviors to a defined noxious cold stimulus (3-12 ºC), including a full-body contraction and the bending of anterior and posterior segments to make a U-Shape. These behaviors are distinct from normal locomotion, responses to gentle touch, noxious heat or harsh mechanical stimuli. Through genetic manipulation, we found cold responses require specific classes of peripheral sensory neurons and receptors, which differ depending on the cold-evoked behavior. Our data indicates these cold-sensing neurons are multimodal, and the level of cellular activation determines the behavioral output to different stimuli.

To study cold nociceptive sensitization, we used a "sunburn assay" which exposes the dorsal side of the larva to UV-damage, and found larvae display a dramatic shift in cold responses after injury. This behavioral shift requires similar sets of peripheral sensory neurons and receptors specific to each sensitized cold-evoked behavior. Lastly, we found the Tumor Necrosis Factor (TNF) and Tachykinin (Tk) pathways, both involved in sensitization to noxious heat, may also play a role UV-induced cold sensitization.

We have established the first system to study noxious cold and cold sensitization in Drosophila. Our unique tool and assay will allow us to further uncover the conserved molecular and genetic players involved in this process.

Keywords

Drosophila, nociception, pain, thermosensation, cold, sensitization, neurons, TRP channels, genetics, neuroscience

Available for download on Wednesday, November 15, 2017

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