Grant: Master's Award: Canada Graduate Scholarships

Chemotherapy (chemo) has contributed in part to an estimated 70 million cancer survivors worldwide. However, chemo has many toxic side effects, such as debilitating fatigue, motor and sensory deterioration, and memory impairment. Chemo-related fatigue is among the most prolonged and common, yet therapeutic interventions remain scarce, and mechanisms unclear. It has been suggested that administering the chemotherapeutic agent, 5-Fluorouracil (5-FU) in rats leads to an inhibition of orexin neurons (ORX). ORX promote arousal, motivation, and locomotor activity- their activation increases energetic states, while their inhibition results in fatigue. Previously, our lab has demonstrated that ORX require astrocytes, a supportive brain cell, for proper functioning, while 5-FU can enter the brain and be metabolized into fluoroacetate, a substance toxic to astrocytes. Therefore, we will investigate if 5-FU inhibits the activity of ORX by impairing astrocyte regulation. Using electrophysiology to record from individual neurons, we have recently found that excitability of ORX was decreased post-5-FU injection in mice. To build on this exciting finding, I will focus on (1) characterizing the influence of 5-FU on the excitability of ORX and (2) the role of astrocytes on the effects following 5-FU. This study will test a single 5-FU injection to identify acute effects, while repeated 5-FU treatments (that mimic standard chemo regimen) will aim to determine long-term effects. This study will be the first to explore the effect of chemo on functional properties of ORX and their astrocytic regulation. This research has the overall aim to provide information on therapeutic targets that could one day relieve fatigue symptoms among millions of individuals.