Abstract

Chemotherapeutic agents, while effective in targeting malignant tumors, often reduce the patients’ quality of life by inducing fatigue, pain, and motivational deficits. These symptoms are collectively referred to as “chemo brain.” The mechanisms underlying these adverse effects, and specifically whether fatigue and motivational impairments share a common etiology, remain poorly understood. The neural–immune substrates of these symptoms remain obscure, in part because standard preclinical regimens either bypass key systemic signals or introduce local toxicity confounds. Here, I establish and validate a three‑day, low‑dose intravenous cisplatin protocol that avoids peritoneal inflammation and severe renal injury yet produces robust, reversible fatigue and increase in effort sensitivity. To delineate the underlying circuitry, I partnered with the WashU Neurotech Hub to develop a wireless, over‑the‑air telemetry system for continuous home‑cage monitoring using in-home-cage behavioral assays for singly housed mice. Finally, I localized activated GFRAL‑expressing and neighboring neurons under this regimen using multiplex cFos and IHC/ISH in the area postrema and nucleus tractus solitarius. Together, these results outline a cytokine‑sensing hindbrain-basal ganglia circuit driven by GDF15-GFRAL signaling, that mediates chemotherapy‑induced motivational decline and points to precise nodes for interventions to preserve patient drive during treatment.

Committee Chair

Adam Kepecs

Committee Members

Marco Pignatelli, Barani Raman

Degree

Master of Science (MS)

Author's Department

Biomedical Engineering

Author's School

McKelvey School of Engineering

Document Type

Thesis

Date of Award

Spring 5-2025

Language

English (en)

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Available for download on Thursday, May 07, 2026

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